Method and devices for treating muscles

ABSTRACT

An apparatus includes multiple first reservoirs and multiple second reservoirs joined with a substrate. Selected ones of the multiple first reservoirs include a reducing agent, and first reservoir surfaces of selected ones of the multiple first reservoirs are proximate to a first substrate surface. Selected ones of the multiple second reservoirs include an oxidizing agent, and second reservoir surfaces of selected ones of the multiple second reservoirs are proximate to the first substrate surface.

RELATED APPLICATIONS

This application is an application under 35 U.S.C. § 371 ofInternational Patent Application PCT/US2016/035540 filed on Jun. 2,2016, which claims the benefit of U.S. provisional patent applicationNo. 62/170,275, filed Jun. 3, 2015, U.S. provisional patent applicationNo. 62/327,202, filed Apr. 25, 2016, and U.S. provisional patentapplication No. 62/327,207, filed Apr. 25, 2016; the disclosures of eachof which are incorporated herein by reference in their entirety.

FIELD

The present specification relates to bioelectric devices designed foruse on certain areas of the body, for example on or around muscles orother contoured areas, and methods of manufacture and use thereof.

SUMMARY

Disclosed herein are systems, devices, and methods for use in treatmentof subjects, in particular treatment of specific areas of tissue, forexample around or about a muscle or muscle group, for example thedeltoids, the triceps, the biceps, the quadriceps, the calf, theshoulder, the abdominals, the back, or the like. Disclosed embodimentscan prevent muscle injury, reduce or repair muscle damage (for example,such as can occur during a workout or athletic performance), improvemuscle function, improve athletic performance, and accelerate musclerecovery, for example by activating enzymes, increasing glucose uptake,driving redox signaling, increasing H₂O₂ production, increasing cellularprotein sulfhydryl levels, and increasing (IGF)-1 R phosphorylation.Embodiments can also up-regulate integrin production and accumulation intreatment areas.

In embodiments the systems, devices, and methods include fabrics, forexample clothing or dressings, for example compression garments orclothing, that comprise one or more biocompatible electrodes configuredto generate at least one of a low level electric field (LLEF) or lowlevel electric current (LLEC). Embodiments disclosed herein can producea uniform current or field density.

Certain embodiments can comprise a solution or formulation comprising anactive agent and a solvent or carrier or vehicle.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a detailed plan view of an embodiment disclosed herein.

FIG. 2 is a detailed plan view of a pattern of applied electricalconductors in accordance with an embodiment disclosed herein.

FIG. 3 is an embodiment using the applied pattern of FIG. 2.

FIG. 4 is a cross-section of FIG. 3 through line 3-3.

FIG. 5 is a detailed plan view of an alternate embodiment disclosedherein which includes fine lines of conductive metal solution connectingelectrodes.

FIG. 6 is a detailed plan view of another alternate embodiment having aline pattern and dot pattern.

FIG. 7 is a detailed plan view of yet another alternate embodimenthaving two line patterns.

FIGS. 8A-8E depict alternate embodiments showing the location ofdiscontinuous regions as well as anchor regions of the system.

FIGS. 9A-9D depict alternate embodiments showing a garment comprising amulti-array matrix of biocompatible microcells.

FIG. 10 depicts alternative embodiments showing body placement ofgarment for treating muscles.

FIGS. 11A-11B depict a “universal” embodiment for use on multiple areasof the body.

FIGS. 12A-12D depict prospective areas for treatment with the universalembodiment in FIG. 11.

FIG. 13 depicts a detailed plan view of a substrate layer electrodepattern disclosed herein.

FIG. 14 depicts a detailed plan view of a substrate layer electrodepattern as disclosed herein.

FIG. 15 depicts a detailed plan view of a substrate layer electrodepattern disclosed herein.

DETAILED DESCRIPTION

Embodiments disclosed herein include systems and devices that canprovide a low level electric field (“LLEF”) to a tissue or organism (a“LLEF system”) or, when brought into contact with an electricallyconducting material, can provide a low level electric current (“LLEC”)to a tissue or organism (a “LLEC system”). Thus, in embodiments a LLECsystem is a LLEF system that is in contact with an electricallyconducting material, for example a liquid material. In certainembodiments, the electric current or electric field can be modulated,for example, to alter the duration, size, shape, field depth, duration,current, polarity, or voltage of the system. For example, it can bedesirable to employ an electric field of greater strength or depth toachieve optimal treatment. In embodiments the watt-density of the systemcan be modulated.

Embodiments disclosed herein include methods of treatment, for exampletreatment of a muscle or muscle group (for example a muscle groupsurrounding a joint), either before, during, or after athletic activityor exercise. For example, a method of treatment disclosed herein cancomprise applying an embodiment disclosed herein to a muscle or musclegroup, then stretching that muscle or muscle group, prior to exercise orathletic performance. Further methods of treatment disclosed herein cancomprise application of an embodiment disclosed herein to a muscle ormuscle group, then stretching that muscle or muscle group, afterexercise or athletic performance. Further methods of treatment disclosedherein can comprise application of an embodiment disclosed herein to amuscle or muscle group while the subject sleeps.

Definitions

“Activation agent” as used herein means a composition useful formaintaining a moist and/or electrically conductive environment withinand about the treatment area. Activation agents can be in the form ofgels or liquids. Activation agents can be conductive. Activation gelscan provide a temperature increase to an area where applied. Activationgels can also be antibacterial.

“Affixing” as used herein can mean contacting a patient or tissue with adevice or system disclosed herein. In embodiments “affixing” can includethe use of straps, elastic, etc.

“Antimicrobial agent” as used herein refers to an additional agent thatkills or inhibits the growth of microorganisms. On type of antimicrobialagent can be an antibacterial agent. “Antibacterial agent” or“antibacterial” as used herein refers to an agent that interferes withthe growth and reproduction of bacteria. Antibacterial agents are usedto disinfect surfaces and eliminate potentially harmful bacteria. Unlikeantibiotics, they are not used as medicines for humans or animals, butare found in products such as soaps, detergents, health and skincareproducts and household cleaners.

“Applied” or “apply” as used herein refers to contacting a surface witha conductive material, for example printing, painting, or spraying aconductive ink on a surface. Alternatively, “applying” can meancontacting a patient or tissue or organism with a device or systemdisclosed herein.

“Compression fabric” as used herein refers to a fabric that displayselastic properties. For example, compression fabrics can comprise lycra,or any suitable material.

“Conductive material” as used herein refers to an object or type ofmaterial which permits the flow of electric charges in one or moredirections. Conductive materials can include solids such as metals orcarbon, or liquids such as conductive metal solutions and conductivegels. Conductive materials can be applied to form at least one matrix.Conductive liquids can dry, cure, or harden after application to form asolid material.

“Discontinuous region” as used herein refers to a “void” in a material(for example a substrate) such as a hole, slot, or the like. The termcan mean any void in the material though typically the void is of aregular shape. A void in the material can be entirely within theperimeter of a material or it can extend to the perimeter of a material.

“Dots” as used herein refers to discrete deposits of similar ordissimilar reservoirs that can function as at least one battery cell.The term can refer to a deposit of any suitable size or shape, such assquares, circles, triangles, lines, etc. The term can be usedsynonymously with, for example, microcells, electrodes, etc.

“Electrode” refers to similar or dissimilar conductive materials. Inembodiments utilizing an external power source the electrodes cancomprise similar conductive materials. In embodiments that do not use anexternal power source, the electrodes can comprise dissimilar conductivematerials that can define an anode and a cathode. Electrodes or dots canbe of similar or dissimilar shapes and sizes, whether or not they aremade of the same material.

“Expandable” as used herein refers to the ability to stretch whileretaining structural integrity and not tearing. The term can refer tosolid regions as well as discontinuous or void regions; solid regions aswell as void regions can stretch or expand.

“Matrix” or “matrices” as used herein refer to a pattern or patterns,such as those formed by electrodes or dots on a surface, such as afabric or a fiber, or the like. Matrices can be designed to vary theelectric field or electric current or microcurrent generated. Forexample, the strength and shape of the field or current or microcurrentcan be altered, or the matrices can be designed to produce an electricfield(s) or current or microcurrent of a desired strength or shape.

“Stretchable” as used herein refers to the ability of embodiments thatstretch without losing their structural integrity. That is, embodimentscan stretch to accommodate irregular skin surfaces or surfaces whereinone portion of the surface can move relative to another portion.

“Treatment” as used herein can include the use of disclosed embodimentson muscles or muscle groups.

LLEC/LLEF Systems, Devices, and Methods of Manufacture

In embodiments, devices disclosed herein comprise patterns ofmicro-batteries that create a field between each dot pair. Inembodiments, the unique field is very short, e.g. in the range ofphysiologic electric fields. In embodiments, the direction of theelectric field produced by disclosed devices is omnidirectional over thetreatment area.

Embodiments of the LLEC or LLEF systems and devices disclosed herein cancomprise electrodes or microcells or reservoirs. Each electrode ormicrocell or reservoir can comprise a conductive metal. In embodiments,the electrodes or microcells can comprise any electrically-conductivematerial, for example, electrically conductive hydrogels, metals,electrolytes, superconductors, semiconductors, plasmas, and nonmetallicconductors such as graphite and conductive polymers. Electricallyconductive metals can include, for example, silver, copper, gold,aluminum, molybdenum, zinc, lithium, tungsten, brass, carbon, nickel,iron, palladium, platinum, tin, bronze, carbon steel, lead, titanium,stainless steel, mercury, Fe/Cr alloys, and the like. The electrode canbe coated or plated with a different metal such as aluminum, gold,platinum or silver.

Dissimilar metals used to make a LLEC or LLEF system disclosed hereincan be silver and zinc, and the electrolytic solution can include sodiumchloride in water. In certain embodiments the electrodes are appliedonto a non-conductive surface to create a pattern, most preferably anarray or multi-array of voltaic cells that do not spontaneously reactuntil they contact an electrolytic solution. Sections of thisdescription use the terms “printing” with “ink,” but it is to beunderstood that the patterns may also be “painted” with “paints.” Theuse of any suitable means for applying a conductive material iscontemplated. In embodiments “ink” or “paint” can comprise any materialsuch as a solution suitable for forming an electrode on a surface suchas a conductive material including a conductive metal solution. Inembodiments “printing” or “painted” can comprise any method of applyinga solution to a material upon which a matrix is desired.

Turning to the figures, in FIG. 1, the dissimilar first electrode 6 andsecond electrode 10 are applied onto a desired primary surface 2 of anarticle 4, for example a fabric. In one embodiment a primary surface isa surface of a LLEC or LLEF system that comes into direct contact withan area to be treated such as a skin surface.

In various embodiments the difference of the standard potentials of theelectrodes or dots or reservoirs can be in a range from about 0.05 V toapproximately about 5.0 V. For example, the standard potential can beabout 0.05 V, about 0.06 V, about 0.07 V, about 0.08 V, about 0.09 V,about 0.1 V, about 0.2 V, about 0.3 V, about 0.4 V, about 0.5 V, about0.6 V, about 0.7 V, about 0.8 V, about 0.9 V, about 1.0 V, about 1.1 V,about 1.2 V, about 1.3 V, about 1.4 V, about 1.5 V, about 1.6 V, about1.7 V, about 1.8 V, about 1.9 V, about 2.0 V, about 2.1 V, about 2.2 V,about 2.3 V, about 2.4 V, about 2.5 V, about 2.6 V, about 2.7 V, about2.8 V, about 2.9 V, about 3.0 V, about 3.1 V, about 3.2 V, about 3.3 V,about 3.4 V, about 3.5 V, about 3.6 V, about 3.7 V, about 3.8 V, about3.9 V, about 4.0 V, about 4.1 V, about 4.2 V, about 4.3 V, about 4.4 V,4.5 V, about 4.6 V, about 4.7 V, 4.8 V, about 4.9 V, about 5.0 V, about5.1 V, about 5.2 V, about 5.3 V, about 5.4 V, about 5.5 V, about 5.6 V,about 5.7 V, about 5.8 V, about 5.9 V, about 6.0 V, about 6.1 V, about6.2 V, about 6.3 V, about 6.4 V, about 6.5 V, about 6.6 V, about 6.7 V,about 6.8 V, about 6.9 V, about 7.0 V, about 7.1 V, about 7.2 V, about7.3 V, about 7.4 V, 7.5 V, about 7.6 V, about 7.7 V, 7.8 V, about 7.9 V,about 8.0 V, about 8.1 V, about 8.2 V, about 8.3 V, about 8.4 V, about8.5 V, about 8.6 V, about 8.7 V, about 8.8 V, about 8.9 V, about 9.0 V,or the like.

In embodiments, systems and devices disclosed herein can produce a lowlevel electric current of between for example about 1 and about 200micro-amperes, between about 10 and about 190 micro-amperes, betweenabout 20 and about 180 micro-amperes, between about 30 and about 170micro-amperes, between about 40 and about 160 micro-amperes, betweenabout 50 and about 150 micro-amperes, between about 60 and about 140micro-amperes, between about 70 and about 130 micro-amperes, betweenabout 80 and about 120 micro-amperes, between about 90 and about 100micro-amperes, between about 100 and about 150 micro-amperes, betweenabout 150 and about 200 micro-amperes, between about 200 and about 250micro-amperes, between about 250 and about 300 micro-amperes, betweenabout 300 and about 350 micro-amperes, between about 350 and about 400micro-amperes, between about 400 and about 450 micro-amperes, betweenabout 450 and about 500 micro-amperes, between about 500 and about 550micro-amperes, between about 550 and about 600 micro-amperes, betweenabout 600 and about 650 micro-amperes, between about 650 and about 700micro-amperes, between about 700 and about 750 micro-amperes, betweenabout 750 and about 800 micro-amperes, between about 800 and about 850micro-amperes, between about 850 and about 900 micro-amperes, betweenabout 900 and about 950 micro-amperes, between about 950 and about 1000micro-amperes (1 milli-amp [mA]), between about 1.0 and about 1.1 mA,between about 1.1 and about 1.2 mA, between about 1.2 and about 1.3 mA,between about 1.3 and about 1.4 mA, between about 1.4 and about 1.5 mA,between about 1.5 and about 1.6 mA, between about 1.6 and about 1.7 mA,between about 1.7 and about 1.8 mA, between about 1.8 and about 1.9 mA,between about 1.9 and about 2.0 mA, between about 2.0 and about 2.1 mA,between about 2.1 and about 2.2 mA, between about 2.2 and about 2.3 mA,between about 2.3 and about 2.4 mA, between about 2.4 and about 2.5 mA,between about 2.5 and about 2.6 mA, between about 2.6 and about 2.7 mA,between about 2.7 and about 2.8 mA, between about 2.8 and about 2.9 mA,between about 2.9 and about 3.0 mA, between about 3.0 and about 3.1 mA,between about 3.1 and about 3.2 mA, between about 3.2 and about 3.3 mA,between about 3.3 and about 3.4 mA, between about 3.4 and about 3.5 mA,between about 3.5 and about 3.6 mA, between about 3.6 and about 3.7 mA,between about 3.7 and about 3.8 mA, between about 3.8 and about 3.9 mA,between about 3.9 and about 4.0 mA, between about 4.0 and about 4.1 mA,between about 4.1 and about 4.2 mA, between about 4.2 and about 4.3 mA,between about 4.3 and about 4.4 mA, between about 4.4 and about 4.5 mA,between about 4.5 and about 5.0 mA, between about 5.0 and about 5.5 mA,between about 5.5 and about 6.0 mA, between about 6.0 and about 6.5 mA,between about 6.5 and about 7.0 mA, between about 7.5 and about 8.0 mA,between about 8.0 and about 8.5 mA, between about 8.5 and about 9.0 mA,between about 9.0 and about 9.5 mA, between about 9.5 and about 10.0 mA,between about 10.0 and about 10.5 mA, between about 10.5 and about 11.0mA, between about 11.0 and about 11.5 mA, between about 11.5 and about12.0 mA, between about 12.0 and about 12.5 mA, between about 12.5 andabout 13.0 mA, between about 13.0 and about 13.5 mA, between about 13.5and about 14.0 mA, between about 14.0 and about 14.5 mA, between about14.5 and about 15.0 mA, or the like.

In embodiments, systems and devices disclosed herein can produce a lowlevel electric current of between for example about 1 and about 400micro-amperes, between about 20 and about 380 micro-amperes, betweenabout 40 and about 360 micro-amperes, between about 60 and about 340micro-amperes, between about 80 and about 320 micro-amperes, betweenabout 100 and about 300 micro-amperes, between about 120 and about 280micro-amperes, between about 140 and about 260 micro-amperes, betweenabout 160 and about 240 micro-amperes, between about 180 and about 220micro-amperes, or the like.

In embodiments, systems and devices disclosed herein can produce a lowlevel electric current of between for example about 1 micro-ampere andabout 1 milli-ampere, between about 50 and about 800 micro-amperes,between about 200 and about 600 micro-amperes, between about 400 andabout 500 micro-amperes, or the like.

In embodiments, systems and devices disclosed herein can produce a lowlevel electric current of about 10 micro-amperes, about 20micro-amperes, about 30 micro-amperes, about 40 micro-amperes, about 50micro-amperes, about 60 micro-amperes, about 70 micro-amperes, about 80micro-amperes, about 90 micro-amperes, about 100 micro-amperes, about110 micro-amperes, about 120 micro-amperes, about 130 micro-amperes,about 140 micro-amperes, about 150 micro-amperes, about 160micro-amperes, about 170 micro-amperes, about 180 micro-amperes, about190 micro-amperes, about 200 micro-amperes, about 210 micro-amperes,about 220 micro-amperes, about 240 micro-amperes, about 260micro-amperes, about 280 micro-amperes, about 300 micro-amperes, about320 micro-amperes, about 340 micro-amperes, about 360 micro-amperes,about 380 micro-amperes, about 400 micro-amperes, about 450micro-amperes, about 500 micro-amperes, about 550 micro-amperes, about600 micro-amperes, about 650 micro-amperes, about 700 micro-amperes,about 750 micro-amperes, about 800 micro-amperes, about 850micro-amperes, about 900 micro-amperes, about 950 micro-amperes, about 1milli-ampere (mA), about 1.1 mA, about 1.2 mA, about 1.3 mA, about 1.4mA, about 1.5 mA, about 1.6 mA, about 1.7 mA, about 1.8 mA, about 1.9mA, about 2.0 mA, about 2.1 mA, about 2.2 mA, about 2.3 mA, about 2.4mA, about 2.5 mA, about 2.6 mA, about 2.7 mA, about 2.8 mA, about 2.9mA, about 3.0 mA, about 3.1 mA, about 3.2 mA, about 3.3 mA, about 3.4mA, about 3.5 mA, about 3.6 mA, about 3.7 mA, about 3.8 mA, about 3.9mA, about 4.0 mA, about 4.1 mA, about 4.2 mA, about 4.3 mA, about 4.4mA, about 4.5 mA, about 4.6 mA, about 4.7 mA, about 4.8 mA, about 4.9mA, about 5.0 mA, about 5.1 mA, about 5.2 mA, about 5.3 mA, about 5.4mA, about 5.5 mA, about 5.6 mA, about 5.7 mA, about 5.8 mA, about 5.9mA, about 6.0 mA, about 6.1 mA, about 4.2 mA, about 6.3 mA, about 6.4mA, about 6.5 mA, about 6.6 mA, about 6.7 mA, about 6.8 mA, about 6.9mA, about 7.0 mA, about 7.1 mA, about 7.2 mA, about 7.3 mA, about 7.4mA, about 7.5 mA, about 7.6 mA, about 7.7 mA, about 7.8 mA, about 7.9mA, about 8.0 mA, about 8.1 mA, about 8.2 mA, about 8.3 mA, about 8.4mA, about 8.5 mA, about 8.6 mA, about 8.7 mA, about 8.8 mA, about 8.9mA, about 9.0 mA, about 9.1 mA, about 9.2 mA, about 9.3 mA, about 9.4mA, about 9.5 mA, about 9.6 mA, about 9.7 mA, about 9.8 mA, about 9.9mA, about 10.0 mA, about 10.1 mA, about 10.2 mA, about 10.3 mA, about10.4 mA, about 10.5 mA, about 10.6 mA, about 10.7 mA, about 10.8 mA,about 10.9 mA, about 11.0 mA, about 11.1 mA, about 11.2 mA, about 11.3mA, about 11.4 mA, about 11.5 mA, about 11.6 mA, about 11.7 mA, about11.8 mA, about 11.9 mA, about 12.0 mA, about 12.1 mA, about 12.2 mA,about 12.3 mA, about 12.4 mA, about 12.5 mA, about 12.6 mA, about 12.7mA, about 12.8 mA, about 12.9 mA, about 13.0 mA, about 13.1 mA, about13.2 mA, about 13.3 mA, about 13.4 mA, about 13.5 mA, about 13.6 mA,about 13.7 mA, about 13.8 mA, about 13.9 mA, about 14.0 mA, about 14.1mA, about 14.2 mA, about 14.3 mA, about 14.4 mA, about 14.5 mA, about14.6 mA, about 14.7 mA, about 14.8 mA, about 14.9 mA, about 15.0 mA,about 15.1 mA, about 15.2 mA, about 15.3 mA, about 15.4 mA, about 15.5mA, about 15.6 mA, about 15.7 mA, about 15.8 mA, or the like.

In embodiments, the disclosed systems and devices can produce a lowlevel electric current of not more than 10 micro-amperes, or not morethan about 20 micro-amperes, not more than about 30 micro-amperes, notmore than about 40 micro-amperes, not more than about 50 micro-amperes,not more than about 60 micro-amperes, not more than about 70micro-amperes, not more than about 80 micro-amperes, not more than about90 micro-amperes, not more than about 100 micro-amperes, not more thanabout 110 micro-amperes, not more than about 120 micro-amperes, not morethan about 130 micro-amperes, not more than about 140 micro-amperes, notmore than about 150 micro-amperes, not more than about 160micro-amperes, not more than about 170 micro-amperes, not more thanabout 180 micro-amperes, not more than about 190 micro-amperes, not morethan about 200 micro-amperes, not more than about 210 micro-amperes, notmore than about 220 micro-amperes, not more than about 230micro-amperes, not more than about 240 micro-amperes, not more thanabout 250 micro-amperes, not more than about 260 micro-amperes, not morethan about 270 micro-amperes, not more than about 280 micro-amperes, notmore than about 290 micro-amperes, not more than about 300micro-amperes, not more than about 310 micro-amperes, not more thanabout 320 micro-amperes, not more than about 340 micro-amperes, not morethan about 360 micro-amperes, not more than about 380 micro-amperes, notmore than about 400 micro-amperes, not more than about 420micro-amperes, not more than about 440 micro-amperes, not more thanabout 460 micro-amperes, not more than about 480 micro-amperes, not morethan about 500 micro-amperes, not more than about 520 micro-amperes, notmore than about 540 micro-amperes, not more than about 560micro-amperes, not more than about 580 micro-amperes, not more thanabout 600 micro-amperes, not more than about 620 micro-amperes, not morethan about 640 micro-amperes, not more than about 660 micro-amperes, notmore than about 680 micro-amperes, not more than about 700micro-amperes, not more than about 720 micro-amperes, not more thanabout 740 micro-amperes, not more than about 760 micro-amperes, not morethan about 780 micro-amperes, not more than about 800 micro-amperes, notmore than about 820 micro-amperes, not more than about 840micro-amperes, not more than about 860 micro-amperes, not more thanabout 880 micro-amperes, not more than about 900 micro-amperes, not morethan about 920 micro-amperes, not more than about 940 micro-amperes, notmore than about 960 micro-amperes, not more than about 980micro-amperes, not more than about 1 milli-ampere (mA), not more thanabout 1.1 mA, not more than about 1.2 mA, not more than about 1.3 mA,not more than about 1.4 mA, not more than about 1.5 mA, not more thanabout 1.6 mA, not more than about 1.7 mA, not more than about 1.8 mA,not more than about 1.9 mA, not more than about 2.0 mA, not more thanabout 2.1 mA, not more than about 2.2 mA, not more than about 2.3 mA,not more than about 2.4 mA, not more than about 2.5 mA, not more thanabout 2.6 mA, not more than about 2.7 mA, not more than about 2.8 mA,not more than about 2.9 mA, not more than about 3.0 mA, not more thanabout 3.1 mA, not more than about 3.2 mA, not more than about 3.3 mA,not more than about 3.4 mA, not more than about 3.5 mA, not more thanabout 3.6 mA, not more than about 3.7 mA, not more than about 3.8 mA,not more than about 3.9 mA, not more than about 4.0 mA, not more thanabout 4.1 mA, not more than about 4.2 mA, not more than about 4.3 mA,not more than about 4.4 mA, not more than about 4.5 mA, not more thanabout 4.6 mA, not more than about 4.7 mA, not more than about 4.8 mA,not more than about 4.9 mA, not more than about 5.0 mA, not more thanabout 5.1 mA, not more than about 5.2 mA, not more than about 5.3 mA,not more than about 5.4 mA, not more than about 5.5 mA, not more thanabout 5.6 mA, not more than about 5.7 mA, not more than about 5.8 mA,not more than about 5.9 mA, not more than about 6.0 mA, not more thanabout 6.1 mA, not more than about 4.2 mA, not more than about 6.3 mA,not more than about 6.4 mA, not more than about 6.5 mA, not more thanabout 6.6 mA, not more than about 6.7 mA, not more than about 6.8 mA,not more than about 6.9 mA, not more than about 7.0 mA, not more thanabout 7.1 mA, not more than about 7.2 mA, not more than about 7.3 mA,not more than about 7.4 mA, not more than about 7.5 mA, not more thanabout 7.6 mA, not more than about 7.7 mA, not more than about 7.8 mA,not more than about 7.9 mA, not more than about 8.0 mA, not more thanabout 8.1 mA, not more than about 8.2 mA, not more than about 8.3 mA,not more than about 8.4 mA, not more than about 8.5 mA, not more thanabout 8.6 mA, not more than about 8.7 mA, not more than about 8.8 mA,not more than about 8.9 mA, not more than about 9.0 mA, not more thanabout 9.1 mA, not more than about 9.2 mA, not more than about 9.3 mA,not more than about 9.4 mA, not more than about 9.5 mA, not more thanabout 9.6 mA, not more than about 9.7 mA, not more than about 9.8 mA,not more than about 9.9 mA, not more than about 10.0 mA, not more thanabout 10.1 mA, not more than about 10.2 mA, not more than about 10.3 mA,not more than about 10.4 mA, not more than about 10.5 mA, not more thanabout 10.6 mA, not more than about 10.7 mA, not more than about 10.8 mA,not more than about 10.9 mA, not more than about 11.0 mA, not more thanabout 11.1 mA, not more than about 11.2 mA, not more than about 11.3 mA,not more than about 11.4 mA, not more than about 11.5 mA, not more thanabout 11.6 mA, not more than about 11.7 mA, not more than about 11.8 mA,not more than about 11.9 mA, not more than about 12.0 mA, not more thanabout 12.1 mA, not more than about 12.2 mA, not more than about 12.3 mA,not more than about 12.4 mA, not more than about 12.5 mA, not more thanabout 12.6 mA, not more than about 12.7 mA, not more than about 12.8 mA,not more than about 12.9 mA, not more than about 13.0 mA, not more thanabout 13.1 mA, not more than about 13.2 mA, not more than about 13.3 mA,not more than about 13.4 mA, not more than about 13.5 mA, not more thanabout 13.6 mA, not more than about 13.7 mA, not more than about 13.8 mA,not more than about 13.9 mA, not more than about 14.0 mA, not more thanabout 14.1 mA, not more than about 14.2 mA, not more than about 14.3 mA,not more than about 14.4 mA, not more than about 14.5 mA, not more thanabout 14.6 mA, not more than about 14.7 mA, not more than about 14.8 mA,not more than about 14.9 mA, not more than about 15.0 mA, not more thanabout 15.1 mA, not more than about 15.2 mA, not more than about 15.3 mA,not more than about 15.4 mA, not more than about 15.5 mA, not more thanabout 15.6 mA, not more than about 15.7 mA, not more than about 15.8 mA,and the like.

In embodiments, systems and devices disclosed herein can produce a lowlevel electric current of not less than 10 micro-amperes, not less than20 micro-amperes, not less than 30 micro-amperes, not less than 40micro-amperes, not less than 50 micro-amperes, not less than 60micro-amperes, not less than 70 micro-amperes, not less than 80micro-amperes, not less than 90 micro-amperes, not less than 100micro-amperes, not less than 110 micro-amperes, not less than 120micro-amperes, not less than 130 micro-amperes, not less than 140micro-amperes, not less than 150 micro-amperes, not less than 160micro-amperes, not less than 170 micro-amperes, not less than 180micro-amperes, not less than 190 micro-amperes, not less than 200micro-amperes, not less than 210 micro-amperes, not less than 220micro-amperes, not less than 230 micro-amperes, not less than 240micro-amperes, not less than 250 micro-amperes, not less than 260micro-amperes, not less than 270 micro-amperes, not less than 280micro-amperes, not less than 290 micro-amperes, not less than 300micro-amperes, not less than 310 micro-amperes, not less than 320micro-amperes, not less than 330 micro-amperes, not less than 340micro-amperes, not less than 350 micro-amperes, not less than 360micro-amperes, not less than 370 micro-amperes, not less than 380micro-amperes, not less than 390 micro-amperes, not less than 400micro-amperes, not less than about 420 micro-amperes, not less thanabout 440 micro-amperes, not less than about 460 micro-amperes, not lessthan about 480 micro-amperes, not less than about 500 micro-amperes, notless than about 520 micro-amperes, not less than about 540micro-amperes, not less than about 560 micro-amperes, not less thanabout 580 micro-amperes, not less than about 600 micro-amperes, not lessthan about 620 micro-amperes, not less than about 640 micro-amperes, notless than about 660 micro-amperes, not less than about 680micro-amperes, not less than about 700 micro-amperes, not less thanabout 720 micro-amperes, not less than about 740 micro-amperes, not lessthan about 760 micro-amperes, not less than about 780 micro-amperes, notless than about 800 micro-amperes, not less than about 820micro-amperes, not less than about 840 micro-amperes, not less thanabout 860 micro-amperes, not less than about 880 micro-amperes, not lessthan about 900 micro-amperes, not less than about 920 micro-amperes, notless than about 940 micro-amperes, not less than about 960micro-amperes, not less than about 980 micro-amperes, not less thanabout 1 milli-ampere (mA), not less than about 1.1 mA, not less thanabout 1.2 mA, not less than about 1.3 mA, not less than about 1.4 mA,not less than about 1.5 mA, not less than about 1.6 mA, not less thanabout 1.7 mA, not less than about 1.8 mA, not less than about 1.9 mA,not less than about 2.0 mA, not less than about 2.1 mA, not less thanabout 2.2 mA, not less than about 2.3 mA, not less than about 2.4 mA,not less than about 2.5 mA, not less than about 2.6 mA, not less thanabout 2.7 mA, not less than about 2.8 mA, not less than about 2.9 mA,not less than about 3.0 mA, not less than about 3.1 mA, not less thanabout 3.2 mA, not less than about 3.3 mA, not less than about 3.4 mA,not less than about 3.5 mA, not less than about 3.6 mA, not less thanabout 3.7 mA, not less than about 3.8 mA, not less than about 3.9 mA,not less than about 4.0 mA, not less than about 4.1 mA, not less thanabout 4.2 mA, not less than about 4.3 mA, not less than about 4.4 mA,not less than about 4.5 mA, not less than about 4.6 mA, not less thanabout 4.7 mA, not less than about 4.8 mA, not less than about 4.9 mA,not less than about 5.0 mA, not less than about 5.1 mA, not less thanabout 5.2 mA, not less than about 5.3 mA, not less than about 5.4 mA,not less than about 5.5 mA, not less than about 5.6 mA, not less thanabout 5.7 mA, not less than about 5.8 mA, not less than about 5.9 mA,not less than about 6.0 mA, not less than about 6.1 mA, not less thanabout 4.2 mA, not less than about 6.3 mA, not less than about 6.4 mA,not less than about 6.5 mA, not less than about 6.6 mA, not less thanabout 6.7 mA, not less than about 6.8 mA, not less than about 6.9 mA,not less than about 7.0 mA, not less than about 7.1 mA, not less thanabout 7.2 mA, not less than about 7.3 mA, not less than about 7.4 mA,not less than about 7.5 mA, not less than about 7.6 mA, not less thanabout 7.7 mA, not less than about 7.8 mA, not less than about 7.9 mA,not less than about 8.0 mA, not less than about 8.1 mA, not less thanabout 8.2 mA, not less than about 8.3 mA, not less than about 8.4 mA,not less than about 8.5 mA, not less than about 8.6 mA, not less thanabout 8.7 mA, not less than about 8.8 mA, not less than about 8.9 mA,not less than about 9.0 mA, not less than about 9.1 mA, not less thanabout 9.2 mA, not less than about 9.3 mA, not less than about 9.4 mA,not less than about 9.5 mA, not less than about 9.6 mA, not less thanabout 9.7 mA, not less than about 9.8 mA, not less than about 9.9 mA,not less than about 10.0 mA, not less than about 10.1 mA, not less thanabout 10.2 mA, not less than about 10.3 mA, not less than about 10.4 mA,not less than about 10.5 mA, not less than about 10.6 mA, not less thanabout 10.7 mA, not less than about 10.8 mA, not less than about 10.9 mA,not less than about 11.0 mA, not less than about 11.1 mA, not less thanabout 11.2 mA, not less than about 11.3 mA, not less than about 11.4 mA,not less than about 11.5 mA, not less than about 11.6 mA, not less thanabout 11.7 mA, not less than about 11.8 mA, not less than about 11.9 mA,not less than about 12.0 mA, not less than about 12.1 mA, not less thanabout 12.2 mA, not less than about 12.3 mA, not less than about 12.4 mA,not less than about 12.5 mA, not less than about 12.6 mA, not less thanabout 12.7 mA, not less than about 12.8 mA, not less than about 12.9 mA,not less than about 13.0 mA, not less than about 13.1 mA, not less thanabout 13.2 mA, not less than about 13.3 mA, not less than about 13.4 mA,not less than about 13.5 mA, not less than about 13.6 mA, not less thanabout 13.7 mA, not less than about 13.8 mA, not less than about 13.9 mA,not less than about 14.0 mA, not less than about 14.1 mA, not less thanabout 14.2 mA, not less than about 14.3 mA, not less than about 14.4 mA,not less than about 14.5 mA, not less than about 14.6 mA, not less thanabout 14.7 mA, not less than about 14.8 mA, not less than about 14.9 mA,not less than about 15.0 mA, not less than about 15.1 mA, not less thanabout 15.2 mA, not less than about 15.3 mA, not less than about 15.4 mA,not less than about 15.5 mA, not less than about 15.6 mA, not less thanabout 15.7 mA, not less than about 15.8 mA, and the like.

In certain embodiments, reservoir or electrode geometry can compriseshapes including circles, polygons, lines, zigzags, ovals, stars, or anysuitable variety. This provides the ability to design/customize surfaceelectric field shapes as well as depth of penetration. For example, inembodiments it can be desirable to employ an electric field of greaterstrength or depth to achieve optimal treatment.

In embodiments, disclosed devices can provide an electric field ofgreater than physiological strength to a depth of, at least 1 mm, 2 mm,3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24mm, 25 mm, 26 mm, 27 mm, 28 mm, 29 mm, 30 mm, 31 mm, 32 mm, 33 mm, 34mm, 35 mm, 36 mm, 37 mm, 38 mm, 39 mm, 40 mm, or more.

Reservoir or electrode or dot sizes and concentrations can vary, asthese variations can allow for changes in the properties of the electricfield created by embodiments of the invention. Certain embodimentsprovide an electric field at about 1 Volt and then, under normal tissueloads with resistance of 100 to 300K ohms, produce a current in therange of 10 microamperes.

Embodiments disclosed herein can comprise patterns of microcells. Thepatterns can be designed to produce an electric field, an electriccurrent, or both, over and through tissue such as human skin or fat ormuscle. In embodiments the pattern can be designed to produce a specificsize, strength, density, shape, or duration of electric field orelectric current. In embodiments reservoir or dot size and separationand configuration can be altered.

In embodiments devices disclosed herein can apply an electric field, anelectric current, or both, wherein the field, current, or both can be ofvarying size, strength, density, shape, or duration, in different areasof the embodiment. In embodiments, by specifically sizing the electrodesor reservoirs, the shape(s) of the electric field(s), electric current,or both can be customized, increasing or decreasing localized wattdensities and allowing for the design of patterns of electrodes orreservoirs wherein the amount of electric field over a tissue can beadjusted based upon feedback from the tissue or upon an algorithm withinsensors operably connected to the embodiment and a control module. Theelectric field, electric current, or both can be greater in one zone ofthe device or system and lesser in another. The electric field, electriccurrent, or both can change with time and be modulated based ontreatment goals or feedback from the tissue or patient. The controlmodule can monitor and adjust the size, strength, density, shape, orduration of electric field or electric current based on tissueparameters. For example, embodiments disclosed herein can produce andmaintain localized electrical events. For example, embodiments disclosedherein can produce specific values for the electric field duration,electric field size, electric field shape, field depth, current,polarity, and/or voltage of the device or system.

Devices disclosed herein can generate a localized electric field in apattern determined by the distance and physical orientation of the dots,cells, or electrodes. Effective depth of the electric field can bepredetermined by the orientation and distance between the cells orelectrodes.

In embodiments the electric field can be extended, for example throughthe use of a hydrogel.

In certain embodiments, for example treatment methods, it can bepreferable to utilize AC or DC current. For example, embodimentsdisclosed herein can employ phased array, pulsed, square wave,sinusoidal, or other wave forms, combinations, or the like. Certainembodiments utilize a controller to produce and control power productionand/or distribution to the device.

A system or device disclosed herein and placed over tissue such as skincan move relative to the tissue. Reducing the amount of motion betweentissue and device can be advantageous to treatment. Slotting or placingcuts into the device can result in less friction or tension on the skin.In embodiments, use of an elastic dressing similar to the elasticity ofthe skin is also disclosed.

Embodiments can include coatings on the surface of the substrate, suchas, for example, over or between the dots, electrodes, or cells. Suchcoatings can include, for example, silicone, an electrolytic mixture,hypoallergenic agents, drugs, biologics, stem cells, skin substitutes,cosmetic products, combinations thereof, or the like. Drugs suitable foruse with embodiments of the invention include analgesics, antibiotics,anti-inflammatories, or the like. Embodiments can include multi-phasesystems, for example wherein one array is on a substrate, and anotherarray is suspended, for example in a gel, for example a hydrogel.

The applied electrodes or reservoirs or dots can adhere or bond to theprimary surface or substrate because a biocompatible binder is mixed, inembodiments into separate mixtures, with each of the dissimilar metalsthat will create the pattern of voltaic cells, in embodiments. Most inksare simply a carrier, and a binder mixed with pigment. Similarly,conductive metal solutions can be a binder mixed with a conductiveelement. The resulting conductive metal solutions can be used with anapplication method such as screen printing to apply the electrodes tothe primary surface in predetermined patterns. Once the conductive metalsolutions dry and/or cure, the patterns of spaced electrodes cansubstantially maintain their relative position, even on a flexiblematerial such as that used for a LLEC or LLEF system. The conductivemetal solution can be allowed to dry before being applied to a surfaceso that the conductive materials do not mix, which could interrupt thearray and cause direct reactions that will release the elements.

In certain embodiments that utilize a poly-cellulose binder, the binderitself can have a beneficial effect such as reducing the localconcentration of matrix metallo-proteases through an iontophoreticprocess that drives the cellulose into the surrounding tissue. Thisprocess can be used to electronically drive other components such asdrugs into the surrounding tissue.

The binder can comprise any biocompatible liquid material that can bemixed with a conductive element (preferably metallic crystals of silveror zinc) to create a conductive solution which can be applied as a thincoating to a microsphere. One suitable binder is a solvent reduciblepolymer, such as the polyacrylic non-toxic silk-screen ink manufacturedby COLORCON® Inc., a division of Berwind Pharmaceutical Services, Inc.(see COLORCON® NO-TOX® product line, part number NT28). In an embodimentthe binder is mixed with high purity (at least 99.99%, in an embodiment)metallic silver crystals to make the silver conductive solution. Thesilver crystals, which can be made by grinding silver into a powder, arepreferably smaller than 100 microns in size or about as fine as flour.In an embodiment, the size of the crystals is about 325 mesh, which istypically about 40 microns in size or a little smaller. The binder isseparately mixed with high purity (at least 99.99%, in an embodiment)metallic zinc powder which has also preferably been sifted throughstandard 325 mesh screen, to make the zinc conductive solution. Incertain embodiments, the dots or electrodes can comprise a metal contentof less than 100%.

Other powders of metal can be used to make other conductive metalsolutions in the same way as described in other embodiments.

The size of the metal crystals, the availability of the surface to theconductive fluid and the ratio of metal to binder affects the releaserate of the metal from the mixture. When COLORCON® polyacrylic ink isused as the binder, about 10 to 40 percent of the mixture should bemetal for a long term bandage (for example, one that stays on for about10 days). For example, for a longer term LLEC or LLEF system the percentof the mixture that should be metal can be 8 percent, or 10 percent, 12percent, 14 percent, 16 percent, 18 percent, 20 percent, 22 percent, 24percent, 26 percent, 28 percent, 30 percent, 32 percent, 34 percent, 36percent, 38 percent, 40 percent, 42 percent, 44 percent, 46 percent, 48percent, 50 percent, or the like.

If the same binder is used, but the percentage of the mixture that ismetal is increased to 60 percent or higher, a typical system will beeffective for longer. For example, for a longer term device, the percentof the mixture that should be metal can be 40 percent, or 42 percent, 44percent, 46 percent, 48 percent, 50 percent, 52 percent, 54 percent, 56percent, 58 percent, 60 percent, 62 percent, 64 percent, 66 percent, 68percent, 70 percent, 72 percent, 74 percent, 76 percent, 78 percent, 80percent, 82 percent, 84 percent, 86 percent, 88 percent, 90 percent, orthe like.

For LLEC or LLEF systems comprising a pliable substrate it can bedesired to decrease the percentage of metal down to 5 percent or less,or to use a binder that causes the crystals to be more deeply embedded,so that the primary surface will be antimicrobial for a very long periodof time and will not wear prematurely. Other binders can dissolve orotherwise break down faster or slower than a polyacrylic ink, soadjustments can be made to achieve the desired rate of spontaneousreactions from the voltaic cells.

To maximize the number of voltaic cells, in various embodiments, apattern of alternating silver masses or electrodes or reservoirs andzinc masses or electrodes or reservoirs can create an array ofelectrical currents across the primary surface. A basic pattern, shownin FIG. 1, has each mass of silver equally spaced from four masses ofzinc, and has each mass of zinc equally spaced from four masses ofsilver, according to an embodiment. The first electrode 6 is separatedfrom the second electrode 10 by a spacing 8. The designs of firstelectrode 6 and second electrode 10 are simply round dots, and in anembodiment, are repeated. Numerous repetitions 12 of the designs resultin a pattern. For an exemplary device comprising silver and zinc, eachsilver design preferably has about twice as much mass as each zincdesign, in an embodiment. For the pattern in FIG. 1, the silver designsare most preferably about a millimeter from each of the closest fourzinc designs, and vice-versa. The resulting pattern of dissimilar metalmasses defines an array of voltaic cells when introduced to anelectrolytic solution. Further disclosure relating to methods ofproducing micro-arrays can be found in U.S. Pat. No. 7,813,806 entitledCURRENT PRODUCING SURFACE FOR TREATING BIOLOGIC TISSUE issued Oct. 12,2010, which is incorporated by reference in its entirety.

A dot pattern of masses like the alternating round dots of FIG. 1 can bepreferred when applying conductive material onto a flexible material,such as those used for an article of clothing such as a shirt, shorts,sleeves, or socks, as the dots won't significantly affect theflexibility of the material. To maximize the density of electricalcurrent over a primary surface the pattern of FIG. 2 can be used. Thefirst electrode 6 in FIG. 2 is a large hexagonally shaped dot, and thesecond electrode 10 is a pair of smaller hexagonally shaped dots thatare spaced from each other. The spacing 8 that is between the firstelectrode 6 and the second electrode 10 maintains a relativelyconsistent distance between adjacent sides of the designs. Numerousrepetitions 12 of the designs result in a pattern 14 that can bedescribed as at least one of the first design being surrounded by sixhexagonally shaped dots of the second design.

FIGS. 3 and 4 show how the pattern of FIG. 2 can be used to make anembodiment disclosed herein. The pattern shown in detail in FIG. 2 isapplied to the primary surface 2 of an embodiment. The back 20 of theprinted material is fixed to a substrate layer 22. This layer isadhesively fixed to a pliable layer 16.

FIG. 5 shows an additional feature, which can be added between designs,that can initiate the flow of current in a poor electrolytic solution. Afine line 24 is printed using one of the conductive metal solutionsalong a current path of each voltaic cell. The fine line will initiallyhave a direct reaction but will be depleted until the distance betweenthe electrodes increases to where maximum voltage is realized. Theinitial current produced is intended to help control edema so that theLLEC system will be effective. If the electrolytic solution is highlyconductive when the system is initially applied the fine line can bequickly depleted and the device will function as though the fine linehad never existed.

FIGS. 6 and 7 show alternative patterns that use at least one linedesign. The first electrode 6 of FIG. 6 is a round dot similar to thefirst design used in FIG. 1. The second electrode 10 of FIG. 6 is aline. When the designs are repeated, they define a pattern of parallellines that are separated by numerous spaced dots. FIG. 7 uses only linedesigns. The first electrode 6 can be thicker or wider than the secondelectrode 10 if the oxidation-reduction reaction requires more metalfrom the first conductive element (mixed into the first design'sconductive metal solution) than the second conductive element (mixedinto the second design's conductive metal solution). The lines can bedashed. Another pattern can be silver grid lines that have zinc massesin the center of each of the cells of the grid. The pattern can beletters printed from alternating conductive materials so that a messagecan be printed onto the primary surface-perhaps a brand name oridentifying information such as patient blood type.

Because the spontaneous oxidation-reduction reaction of silver and zincuses a ratio of approximately two silver to one zinc, the silver designcan contain about twice as much mass as the zinc design in anembodiment. At a spacing of about 1 mm between the closest dissimilarmetals (closest edge to closest edge) each voltaic cell that contacts aconductive fluid such as a cosmetic cream can create approximately 1volt of potential that will penetrate substantially through itssurrounding surfaces. Closer spacing of the dots can decrease theresistance, providing less potential, and the current will not penetrateas deeply. Therefore, spacing between the closest conductive materialscan be, for example, 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19μm, 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29μm, 30 μm, 31 μm, 32 μm, 33 μm, 34 μm, 35 μm, 36 μm, 37 μm, 38 μm, 39μm, 40 μm, 41 μm, 42 μm, 43 μm, 44 μm, 45 μm, 46 μm, 47 μm, 48 μm, 49μm, 50 μm, 51 μm, 52 μm, 53 μm, 54 μm, 55 μm, 56 μm, 57 μm, 58 μm, 59μm, 60 μm, 61 μm, 62 μm, 63 μm, 64 μm, 65 μm, 66 μm, 67 μm, 68 μm, 69μm, 70 μm, 71 μm, 72 μm, 73 μm, 74 μm, 75 μm, 76 μm, 77 μm, 78 μm, 79μm, 80 μm, 81 μm, 82 μm, 83 μm, 84 μm, 85 μm, 86 μm, 87 μm, 88 μm, 89μm, 90 μm, 91 μm, 92 μm, 93 μm, 94 μm, 95 μm, 96 μm, 97 μm, 98 μm, 99μm, 0.1 mm, or 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm,0.9 mm, 1 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm,1.8 mm, 1.9 mm, 2 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm,2.7 mm, 2.8 mm, 2.9 mm, 3 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm,3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, 4 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm,4.5 mm, 4.6 mm, 4.7 mm, 4.8 mm, 4.9 mm, 5 mm, 5.1 mm, 5.2 mm, 5.3 mm,5.4 mm, 5.5 mm, 5.6 mm, 5.7 mm, 5.8 mm, 5.9 mm, 6 mm, or the like.

In certain embodiments the spacing between the closest conductivematerials can be not more than 0.1 mm, or not more than 0.2 mm, not morethan 0.3 mm, not more than 0.4 mm, not more than 0.5 mm, not more than0.6 mm, not more than 0.7 mm, not more than 0.8 mm, not more than 0.9mm, not more than 1 mm, not more than 1.1 mm, not more than 1.2 mm, notmore than 1.3 mm, not more than 1.4 mm, not more than 1.5 mm, not morethan 1.6 mm, not more than 1.7 mm, not more than 1.8 mm, not more than1.9 mm, not more than 2 mm, not more than 2.1 mm, not more than 2.2 mm,not more than 2.3 mm, not more than 2.4 mm, not more than 2.5 mm, notmore than 2.6 mm, not more than 2.7 mm, not more than 2.8 mm, not morethan 2.9 mm, not more than 3 mm, not more than 3.1 mm, not more than 3.2mm, not more than 3.3 mm, not more than 3.4 mm, not more than 3.5 mm,not more than 3.6 mm, not more than 3.7 mm, not more than 3.8 mm, notmore than 3.9 mm, not more than 4 mm, not more than 4.1 mm, not morethan 4.2 mm, not more than 4.3 mm, not more than 4.4 mm, not more than4.5 mm, not more than 4.6 mm, not more than 4.7 mm, not more than 4.8mm, not more than 4.9 mm, not more than 5 mm, not more than 5.1 mm, notmore than 5.2 mm, not more than 5.3 mm, not more than 5.4 mm, not morethan 5.5 mm, not more than 5.6 mm, not more than 5.7 mm, not more than5.8 mm, not more than 5.9 mm, not more than 6 mm, or the like.

In certain embodiments spacing between the closest conductive materialscan be not less than 0.1 mm, or not less than 0.2 mm, not less than 0.3mm, not less than 0.4 mm, not less than 0.5 mm, not less than 0.6 mm,not less than 0.7 mm, not less than 0.8 mm, not less than 0.9 mm, notless than 1 mm, not less than 1.1 mm, not less than 1.2 mm, not lessthan 1.3 mm, not less than 1.4 mm, not less than 1.5 mm, not less than1.6 mm, not less than 1.7 mm, not less than 1.8 mm, not less than 1.9mm, not less than 2 mm, not less than 2.1 mm, not less than 2.2 mm, notless than 2.3 mm, not less than 2.4 mm, not less than 2.5 mm, not lessthan 2.6 mm, not less than 2.7 mm, not less than 2.8 mm, not less than2.9 mm, not less than 3 mm, not less than 3.1 mm, not less than 3.2 mm,not less than 3.3 mm, not less than 3.4 mm, not less than 3.5 mm, notless than 3.6 mm, not less than 3.7 mm, not less than 3.8 mm, not lessthan 3.9 mm, not less than 4 mm, not less than 4.1 mm, not less than 4.2mm, not less than 4.3 mm, not less than 4.4 mm, not less than 4.5 mm,not less than 4.6 mm, not less than 4.7 mm, not less than 4.8 mm, notless than 4.9 mm, not less than 5 mm, not less than 5.1 mm, not lessthan 5.2 mm, not less than 5.3 mm, not less than 5.4 mm, not less than5.5 mm, not less than 5.6 mm, not less than 5.7 mm, not less than 5.8mm, not less than 5.9 mm, not less than 6 mm, or the like.

Disclosures of the present specification include LLEC or LLEF systemscomprising a primary surface of a material wherein the material isadapted to be applied to an area of tissue such as a muscle; a firstelectrode design formed from a first conductive liquid that includes amixture of a polymer and a first element, the first conductive liquidbeing applied into a position of contact with the primary surface, thefirst element including a metal species, and the first electrode designincluding at least one dot or reservoir, wherein selective ones of theat least one dot or reservoir have approximately a 1.5 mm+/−1 mm meandiameter; a second electrode design formed from a second conductiveliquid that includes a mixture of a polymer and a second element, thesecond element including a different metal species than the firstelement, the second conductive liquid being printed into a position ofcontact with the primary surface, and the second electrode designincluding at least one other dot or reservoir, wherein selective ones ofthe at least one other dot or reservoir have approximately a 2.5 mm+/−2mm mean diameter; a spacing on the primary surface that is between thefirst electrode design and the second electrode design such that thefirst electrode design does not physically contact the second electrodedesign, wherein the spacing is approximately 1.5 mm+/−1 mm, and at leastone repetition of the first electrode design and the second electrodedesign, the at least one repetition of the first electrode design beingsubstantially adjacent the second electrode design, wherein the at leastone repetition of the first electrode design and the second electrodedesign, in conjunction with the spacing between the first electrodedesign and the second electrode design, defines at least one pattern ofat least one voltaic cell for spontaneously generating at least oneelectrical current when introduced to an electrolytic solution.Therefore, electrodes, dots or reservoirs can have a mean diameter of0.2 mm, or 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.0mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9mm, 2.0 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8mm, 2.9 mm, 3.0 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.7mm, 3.8 mm, 3.9 mm, 4.0 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, 4.5 mm, 4.6mm, 4.7 mm, 4.8 mm, 4.9 mm, 5.0 mm, or the like.

In further embodiments, electrodes, dots or reservoirs can have a meandiameter of not less than 0.2 mm, or not less than 0.3 mm, not less than0.4 mm, not less than 0.5 mm, not less than 0.6 mm, not less than 0.7mm, not less than 0.8 mm, not less than 0.9 mm, not less than 1.0 mm,not less than 1.1 mm, not less than 1.2 mm, not less than 1.3 mm, notless than 1.4 mm, not less than 1.5 mm, not less than 1.6 mm, not lessthan 1.7 mm, not less than 1.8 mm, not less than 1.9 mm, not less than2.0 mm, not less than 2.1 mm, not less than 2.2 mm, not less than 2.3mm, not less than 2.4 mm, not less than 2.5 mm, not less than 2.6 mm,not less than 2.7 mm, not less than 2.8 mm, not less than 2.9 mm, notless than 3.0 mm, not less than 3.1 mm, not less than 3.2 mm, not lessthan 3.3 mm, not less than 3.4 mm, not less than 3.5 mm, not less than3.6 mm, not less than 3.7 mm, not less than 3.8 mm, not less than 3.9mm, not less than 4.0 mm, not less than 4.1 mm, not less than 4.2 mm,not less than 4.3 mm, not less than 4.4 mm, not less than 4.5 mm, notless than 4.6 mm, not less than 4.7 mm, not less than 4.8 mm, not lessthan 4.9 mm, not less than 5.0 mm, or the like.

In further embodiments, electrodes, dots or reservoirs can have a meandiameter of not more than 0.2 mm, or not more than 0.3 mm, not more than0.4 mm, not more than 0.5 mm, not more than 0.6 mm, not more than 0.7mm, not more than 0.8 mm, not more than 0.9 mm, not more than 1.0 mm,not more than 1.1 mm, not more than 1.2 mm, not more than 1.3 mm, notmore than 1.4 mm, not more than 1.5 mm, not more than 1.6 mm, not morethan 1.7 mm, not more than 1.8 mm, not more than 1.9 mm, not more than2.0 mm, not more than 2.1 mm, not more than 2.2 mm, not more than 2.3mm, not more than 2.4 mm, not more than 2.5 mm, not more than 2.6 mm,not more than 2.7 mm, not more than 2.8 mm, not more than 2.9 mm, notmore than 3.0 mm, not more than 3.1 mm, not more than 3.2 mm, not morethan 3.3 mm, not more than 3.4 mm, not more than 3.5 mm, not more than3.6 mm, not more than 3.7 mm, not more than 3.8 mm, not more than 3.9mm, not more than 4.0 mm, not more than 4.1 mm, not more than 4.2 mm,not more than 4.3 mm, not more than 4.4 mm, not more than 4.5 mm, notmore than 4.6 mm, not more than 4.7 mm, not more than 4.8 mm, not morethan 4.9 mm, not more than 5.0 mm, or the like.

The material concentrations or quantities within and/or the relativesizes (e.g., dimensions or surface area) of the first and secondreservoirs can be selected deliberately to achieve variouscharacteristics of the systems' behavior. For example, the quantities ofmaterial within a first and second reservoir can be selected to providean apparatus having an operational behavior that depletes atapproximately a desired rate and/or that “dies” after an approximateperiod of time after activation. In an embodiment the one or more firstreservoirs and the one or more second reservoirs are configured tosustain one or more currents for an approximate pre-determined period oftime, after activation. It is to be understood that the amount of timethat currents are sustained can depend on external conditions andfactors (e.g., the quantity and type of activation material), andcurrents can occur intermittently depending on the presence or absenceof activation material. Further disclosure relating to producingreservoirs that are configured to sustain one or more currents for anapproximate pre-determined period of time can be found in U.S. Pat. No.7,904,147 entitled SUBSTANTIALLY PLANAR ARTICLE AND METHODS OFMANUFACTURE issued Mar. 8, 2011, which is incorporated by referenceherein in its entirety.

In various embodiments the difference of the standard potentials of thefirst and second reservoirs can be in a range from about 0.05 V toapproximately 5.0 V. For example, the standard potential can be 0.05 V,or 0.06 V, 0.07 V, 0.08 V, 0.09 V, 0.1 V, 0.2 V, 0.3 V, 0.4 V, 0.5 V,0.6 V, 0.7 V, 0.8 V, 0.9 V, 1.0 V, 1.1 V, 1.2 V, 1.3 V, 1.4 V, 1.5 V,1.6 V, 1.7 V, 1.8 V, 1.9 V, 2.0 V, 2.1 V, 2.2 V, 2.3 V, 2.4 V, 2.5 V,2.6 V, 2.7 V, 2.8 V, 2.9 V, 3.0 V, 3.1 V, 3.2 V, 3.3 V, 3.4 V, 3.5 V,3.6 V, 3.7 V, 3.8 V, 3.9 V, 4.0 V, 4.1 V, 4.2 V, 4.3 V, 4.4 V, 4.5 V,4.6 V, 4.7 V, 4.8 V, 4.9 V, 5.0 V, or the like.

In a particular embodiment, the difference between the standardpotentials of the first and second reservoirs can be at least 0.05 V, orat least 0.06 V, at least 0.07 V, at least 0.08 V, at least 0.09 V, atleast 0.1 V, at least 0.2 V, at least 0.3 V, at least 0.4 V, at least0.5 V, at least 0.6 V, at least 0.7 V, at least 0.8 V, at least 0.9 V,at least 1.0 V, at least 1.1 V, at least 1.2 V, at least 1.3 V, at least1.4 V, at least 1.5 V, at least 1.6 V, at least 1.7 V, at least 1.8 V,at least 1.9 V, at least 2.0 V, at least 2.1 V, at least 2.2 V, at least2.3 V, at least 2.4 V, at least 2.5 V, at least 2.6 V, at least 2.7 V,at least 2.8 V, at least 2.9 V, at least 3.0 V, at least 3.1 V, at least3.2 V, at least 3.3 V, at least 3.4 V, at least 3.5 V, at least 3.6 V,at least 3.7 V, at least 3.8 V, at least 3.9 V, at least 4.0 V, at least4.1 V, at least 4.2 V, at least 4.3 V, at least 4.4 V, at least 4.5 V,at least 4.6 V, at least 4.7 V, at least 4.8 V, at least 4.9 V, at least5.0 V, or the like.

In a particular embodiment, the difference of the standard potentials ofthe first and second reservoirs can be not more than 0.05 V, or not morethan 0.06 V, not more than 0.07 V, not more than 0.08 V, not more than0.09 V, not more than 0.1 V, not more than 0.2 V, not more than 0.3 V,not more than 0.4 V, not more than 0.5 V, not more than 0.6 V, not morethan 0.7 V, not more than 0.8 V, not more than 0.9 V, not more than 1.0V, not more than 1.1 V, not more than 1.2 V, not more than 1.3 V, notmore than 1.4 V, not more than 1.5 V, not more than 1.6 V, not more than1.7 V, not more than 1.8 V, not more than 1.9 V, not more than 2.0 V,not more than 2.1 V, not more than 2.2 V, not more than 2.3 V, not morethan 2.4 V, not more than 2.5 V, not more than 2.6 V, not more than 2.7V, not more than 2.8 V, not more than 2.9 V, not more than 3.0 V, notmore than 3.1 V, not more than 3.2 V, not more than 3.3 V, not more than3.4 V, not more than 3.5 V, not more than 3.6 V, not more than 3.7 V,not more than 3.8 V, not more than 3.9 V, not more than 4.0 V, not morethan 4.1 V, not more than 4.2 V, not more than 4.3 V, not more than 4.4V, not more than 4.5 V, not more than 4.6 V, not more than 4.7 V, notmore than 4.8 V, not more than 4.9 V, not more than 5.0 V, or the like.In embodiments that include very small reservoirs (e.g., on thenanometer scale), the difference of the standard potentials can besubstantially less or more. Further disclosure relating to standardpotentials can be found in U.S. Pat. No. 8,224,439 entitled BATTERIESAND METHODS OF MANUFACTURE AND USE issued Jul. 17, 2012, which isincorporated by reference herein in its entirety.

The voltage present at the site of treatment is typically in the rangeof millivolts, but disclosed embodiments can introduce a much highervoltage, for example near 1 volt when using the 1 mm spacing ofdissimilar metals already described. The higher voltage is believed todrive the current deeper into the treatment area. In this way thecurrent not only can drive silver and zinc into the treatment if desiredfor treatment, but the current can also provide a stimulatory current sothat the entire surface area can be treated. The higher voltage may alsoincrease antimicrobial effect bacteria and preventing biofilms. Theelectric field can also have beneficial effects on cell migration, ATPproduction, and angiogenesis.

Embodiments disclosed herein relating to tissue treatment can alsocomprise selecting a patient or tissue in need of, or that could benefitby, the methods described herein.

In embodiments the fabric or dressing can include a port to access theinterior, for example to add fluid, gel, cosmetic products, a hydratingmaterial, or some other material to the dressing. Certain embodimentscan comprise a “blister” top that can enclose a material such as anantibacterial or a hydrating medium. In embodiments, the blister top cancontain a material that is released into or on to the material when theblister is pressed, for example a liquid or cream. For example,embodiments disclosed herein can comprise a blister top containing anantibacterial or the like.

In embodiments the system comprises a component such as lycra or spandexor elastic or other such fabric to maintain or help maintain itsposition. In certain embodiment the system comprises a compressionfabric and exerts a pressure on subject's body. In general, thecompression garments described herein may be configured to exert apressure of between about 2 mm Hg and about 100 mmHg on a surface. Inembodiments the pressure applied by the garment can be, for example,between 5 and 90 mmHg, between 10 and 80 mmHg, between 15 and 75 mmHg,between 20 and 70 mmHg, between 25 and 65 mmHg, between 30 and 60 mmHg,between 35 and 55 mmHg, between 40 and 50 mmHg, or the like.

In other embodiments the pressure exerted on subject's body can vary bythe type of garment type and the type of tissue injury. For example, agarment shaped to fit a patient's leg can be configured to exert agreater or lesser compression force on the quadriceps than on the lowerleg. Additionally, a tissue injury such as a torn rotor cuff ortreatment accompanying post tenotomy surgery can require a specificamount of pressure exerted on the tissue injury to keep the tissue orjoint immobilized while healing. In this example, a garment or dressingcan be shaped to fit the area of the patient's injury and exert agreater or less compression force as prescribed compared to the rest ofthe garment or dressing.

In embodiments, disclosed systems and/or devices can comprise componentssuch as straps to maintain or help maintain its position. In certainembodiments the system or device comprises a strap on either end of thelong axis, or a strap linking on end of the long axis to the other. Inembodiments that straps can comprise Velcro or a similar fasteningsystem. In embodiments the straps can comprise elastic materials. Infurther embodiments the strap can comprise a conductive material, forexample a wire or cable to electrically link the device with othercomponents, such as monitoring equipment or a power source.

Aspects disclosed herein include systems, devices, and methods for datacollection and/or data transmission, for example using bioelectricdevices that comprise a substrate with one or more sensing elements,multi-array matrix of biocompatible microcells which can generate a LLEFor LLEC, and wherein a data element is collected from the sensingelement and transmitted by a control module to a external device.Embodiments can include, for example, data collection equipment so as totrack and/or quantify a user's movements or performance. Embodiments caninclude, for example, an accelerometer, so as to measure a user's speed,or impact forces on a user. Embodiments can include optical datacollection devices, for example a camera.

In embodiments the device can be mechanically or wirelessly linked tomonitoring or data collection equipment, for example linked viaBluetooth to a cell phone or computer that collects data from thedevice. In certain embodiments, disclosed devices and systems cancomprise data collection means, such as location, temperature, pH,pressure, or conductivity data collection means. Embodiments cancomprise a display, for example to visually present, for example, thelocation, temperature, pH, pressure, or conductivity data to a user.

In embodiments, the visual display can indicate when a data reading isoutside a desired or approved range. For example, in an embodiment thedevice can provide a visual or audible warning or alarm when anaccelerometer reading indicates an impact greater than the desiredrange, or a visual or audible warning or alarm when a temperature,pulse, or respiration reading is outside a desired range.

In certain embodiments, a substrate comprising the multi-array matrixcan comprise one layer of a composite dressing, for example a compositegarment or fabric comprising the substrate, an adhesive layer, anexpandable absorbent layer, and a stretchable, expandable film layer.The expandable absorbent layer can absorb excess fluid such asperspiration from the substrate and expand away from the treatment area,thus preventing oversaturation of the treatment area with resultantmaceration and increased infection risk.

The stretchable, expandable film layer can stretch to accommodate alarger foam volume as the foam absorbs liquid. This aspect reduces shearforces on the skin. Additionally, the vertically-expanding foam and filmallows the dressing to absorb more volume of fluid in a smaller contactarea.

In embodiments the system comprises a component such as an adhesive tomaintain or help maintain its position. The adhesive component can becovered with a protective layer that can be removed to expose theadhesive at the time of use. In embodiments the adhesive can comprise,for example, sealants, such as hypoallergenic sealants, waterproofsealants such as epoxies, and the like. Straps can include Velcro orsimilar materials to aid in maintaining the position of the device.

In embodiments the positioning component can comprise an elastic filmwith an elasticity, for example, similar to that of skin, or greaterthan that of skin, or less than that of skin. In embodiments, the LLECor LLEF system can comprise a laminate where layers of the laminate canbe of varying elasticities. For example, an outer layer may be highlyelastic and an inner layer in-elastic or less elastic. The in-elasticlayer can be made to stretch by placing stress relieving discontinuousregions or slits through the thickness of the material so there is amechanical displacement rather than stress that would break the fabricweave before stretching would occur. In embodiments the slits can extendcompletely through a layer or the system or can be placed whereexpansion is required. In embodiments of the system the slits do notextend all the way through the system or a portion of the system such asthe substrate. In embodiments the discontinuous regions can pass halfwaythrough the long axis of the substrate.

In embodiments the device can be shaped to fit an area of desired use,for example a muscle, such as cardiac muscle, smooth muscle, or skeletalmuscle.

Embodiments disclosed herein comprise biocompatible electrodes orreservoirs or dots on a surface or substrate, for example a fabric, afiber, or the like. In embodiments the surface or substrate can bepliable, for example to better follow the contours of an area to betreated, such as the face or back. In embodiments the surface orsubstrate can comprise a gauze or mesh or plastic. Suitable types ofpliable surfaces or substrates for use in embodiments disclosed hereincan be absorbent or non-absorbent textiles, low-adhesives, vaporpermeable films, hydrocolloids, hydrogels, alginates, foams, foam-basedmaterials, cellulose-based materials including Kettenbach fibers, hollowtubes, fibrous materials, such as those impregnated withanhydrous/hygroscopic materials, beads and the like, or any suitablematerial as known in the art. In embodiments the pliable material canform, for example, a mask, such as that worn on the body, pants, shorts,gloves, socks, shirts or a portion thereof, for example an elastic orcompression shirt, or a portion thereof such as a sleeve, wrappings,towels, cloths, fabrics, or the like. Multi layer embodiments caninclude, for example, a skin-contacting layer, a hydration layer, and ahydration containment layer.

In embodiments the substrate layer can be non-pliable, for example, aplastic such as a pad (for example a shoulder or thigh pad) or a helmetor the like.

A LLEC or LLEF system disclosed herein can comprise “anchor” regions or“arms” or straps to affix the system securely. The anchor regions orarms can anchor the LLEC or LLEF system. For example, a LLEC or LLEFsystem can be secured to an area proximal to a treatment area, andanchor regions of the system can extend to areas of minimal stress ormovement to securely affix the system. Further, the LLEC system canreduce stress on an area, for example by “countering” the physicalstress caused by movement.

In embodiments the LLEC or LLEF system can comprise additional materialsto aid in treatment, for example a warming gel.

In embodiments, the LLEC or LLEF system can comprise instructions ordirections on how to place the system to maximize its performance.Embodiments include a kit comprising an LLEC or LLEF system anddirections for its use. Embodiments can include software to integratethe system or device with, for example, a computer, or cellulartelephone, or the like.

In certain embodiments dissimilar or similar metals can be used tocreate an electric field with a desired voltage. In certain embodimentsthe pattern of reservoirs can control the watt density and shape of theelectric field.

Certain embodiments can utilize a power source, for example a battery.The power source can be any energy source capable of generating acurrent in the LLEC system and can include, for example, AC power, DCpower, radio frequencies (RF) such as pulsed RF, induction, ultrasound,and the like. For example, an AC power source can be of any wave form,such as a sine wave, a triangular wave, or a square wave. AC power canalso be of any frequency such as for example 50 Hz, or 60 HZ, or thelike. AC power can also be of any voltage, such as for example 120volts, or 220 volts, or the like. In embodiments an AC power source canbe electronically modified, such as for example having the voltagereduced, prior to use.

In embodiments the electric field can be extended, for example throughthe use of a hydrogel. A hydrogel is a network of polymer chains thatare hydrophilic. Hydrogels are highly absorbent natural or syntheticpolymeric networks. Hydrogels can be configured to contain a highpercentage of water (e.g. they can contain over 90% water). Hydrogelscan possess a degree of flexibility very similar to natural tissue, dueto their significant water content. A hydrogel can be configured in avariety of viscosities. Viscosity is a measurement of a fluid ormaterial's resistance to gradual deformation by shear stress or tensilestress. In embodiments the electrical field can be extended through asemi-liquid hydrogel with a low viscosity such an ointment or a cellularculture medium. In other embodiments the electrical field can beextended through a solid hydrogel with a high viscosity such as a Petridish, clothing, or material used to manufacture a prosthetic. Ingeneral, the hydrogel described herein may be configured to a viscosityof between about 0.5 Pa·s and greater than about 10¹² Pa·s. Inembodiments the viscosity of a hydrogel can be, for example, between 0.5and 10¹² Pa·s, between 1 Pa·s and 10⁶ Pa·s, between 5 and 10³ Pa·s,between 10 and 100 Pa·s, between 15 and 90 Pa·s, between 20 and 80 Pa·s,between 25 and 70 Pa·s, between 30 and 60 Pa·s, or the like. Inembodiments, the hydrogel can comprise electrolytes to increase theirconductivity.

While various embodiments have been shown and described, it will berealized that alterations and modifications can be made thereto withoutdeparting from the scope of the following claims. It is expected thatother methods of applying the conductive material can be substituted asappropriate. Also, there are numerous shapes, sizes and patterns ofvoltaic cells that have not been described but it is expected that thisdisclosure will enable those skilled in the art to incorporate their owndesigns which will then be applied to a surface to create voltaic cellswhich will become active when brought into contact with an electrolyticsolution.

Certain embodiments include LLEC or LLEF systems comprising embodimentsdesigned to be used on irregular, non-planar, or “stretching” surfaces.Embodiments disclosed herein can be used with numerous irregularsurfaces of the body or areas prone to movement, for example theshoulders, the back, the legs, the arms, etc.

In certain embodiments comprising a garment, the garment can be shapedto fit a particular region of the body such as an arm, shoulder, elbow,leg, knee, hip, ankle, or chest. Additionally, a garment can be acompression fabric and can exert a pressure on a subject's body surfaceto allow stable and continuous positioning of the garment substrate onsubject's body.

FIG. 9A depicts an example garment 900 comprising a multi-array matrixof biocompatible microcells. Garment 900 comprises electrodes 901 andsubstrate 902. Electrodes 901 are printed around the entirety ofsubstrate 902 including the back of garment 910. Electrodes 901 canprovide a LLEF to tissue, and, when in contact with a conductivematerial, a LLEC. In another embodiment, electrodes 901 can be printedto a portion of the garment 950, as depicted in FIG. 9B. For example,electrodes 901 can be applied to only the back of garment 960 to provideLLEF to lower back. In certain embodiment, electrodes 901 can also beremoved and a new set of dots 901 can be applied to similar or newlocation on garment (950 & 960). The array can be printed or appliedsuch that it contacts the skin while in use. For example, the array canbe printed on or applied to the inside of the garment.

FIG. 10 depicts alternative embodiments showing exemplary garment bodyplacement for treating muscles. In certain embodiments, garments can beconfigured to be worn over the torso, such as the thoracic, dorsal(back), abdominal, pelvic, pubic, or a combination thereof. In certainembodiments, garment can also be configured to be worn over theextremities, such upper limbs and lower limbs. In certain embodiments,garments can also be configured to be worn over the head, neck, or acombination thereof. Additionally, certain embodiments can be configuredto include multiple combinations of the torso, extremities, cephalic,and cervical areas.

FIG. 11 shows a “universal” embodiment as disclosed herein. The designof the embodiment provides for compatibility with numerous areas of thebody. FIG. 12 shows prospective treatment areas using the universalembodiment.

FIG. 13 shows an embodiment utilizing two electrodes (one positive andone negative). Upper arms 140 and 145 can be, for example, 1, 2, 3, or 4mm in width. Lower arm 147 and serpentine 149 can be, for example, 1, 2,3, or 4 mm in width. The electrodes can be, for example, 1, 2, or 3 mmin depth.

FIG. 14 shows an embodiment utilizing two electrodes (one positive andone negative). Upper arms 150 and 155 can be, for example, 1, 2, 3, or 4mm in width. The extensions protruding from the lower arm 156 can be,for example, 1, 1.5, 2, 2.5, 3, 3.5, or 4 mm in width. The extensionsprotruding from the comb 158 can be, for example, 1, 2, 3, 4, 5, 6, or 7mm in width. The electrodes can be, for example, 1, 2, or 3 mm in depth.

FIG. 15 shows an embodiment utilizing two electrodes (one positive andone negative). Upper arms 160 and 165 can be, for example, 1, 2, 3, or 4mm in width. Lower block 167 can be, for example, 30, 32, 34, 36, 38,40, 42, 44, 46, 48, 50, 52, or 54 mm along its shorter axis. Lower block167 can be, for example, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mm alongits longer axis. The electrodes can be, for example, 1, 2, or 3 mm indepth.

In embodiments such as those in FIGS. 14-16, the width and depth of thevarious areas of the electrode can be designed to produce a particularelectric field, or, when both electrodes are in contact with aconductive material, a particular electric current. For example, thewidth of the various areas of the electrode can be, for example, 0.1 mm,or 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1 mm,1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm,2 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm,2.9 mm, 3 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.7 mm,3.8 mm, 3.9 mm, 4 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, 4.5 mm, 4.6 mm,4.7 mm, 4.8 mm, 4.9 mm, 5 mm, 5.1 mm, 5.2 mm, 5.3 mm, 5.4 mm, 5.5 mm,5.6 mm, 5.7 mm, 5.8 mm, 5.9 mm, 6 mm, or 7 mm, or 8 mm, or 9 mm, or 10mm, or 11 mm, or the like.

In embodiments, the depth or thickness of the various areas of theelectrode can be, for example, 0.1 mm, or 0.2 mm, 0.3 mm, 0.4 mm, 0.5mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2 mm, 2.1 mm, 2.2 mm, 2.3mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3 mm, 3.1 mm, 3.2mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, 4 mm, 4.1mm, 4.2 mm, 4.3 mm, 4.4 mm, 4.5 mm, 4.6 mm, 4.7 mm, 4.8 mm, 4.9 mm, 5mm, 5.1 mm, 5.2 mm, 5.3 mm, 5.4 mm, 5.5 mm, 5.6 mm, 5.7 mm, 5.8 mm, 5.9mm, 6 mm, or the like.

The shortest distance between the two electrodes in an embodiment canbe, for example, 0.1 mm, or 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7mm, 0.8 mm, 0.9 mm, 1 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6mm, 1.7 mm, 1.8 mm, 1.9 mm, 2 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4mm, 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, 4 mm, 4.1 mm, 4.2 mm, 4.3mm, 4.4 mm, 4.5 mm, 4.6 mm, 4.7 mm, 4.8 mm, 4.9 mm, 5 mm, 5.1 mm, 5.2mm, 5.3 mm, 5.4 mm, 5.5 mm, 5.6 mm, 5.7 mm, 5.8 mm, 5.9 mm, 6 mm, 7 mm,8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 28mm, 29 mm, 30 mm, 31 mm, 32 mm, 33 mm, 34 mm, or the like.

In embodiments, the length of the long axis of the device can be, forexample, 2 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm,2.8 mm, 2.9 mm, 3 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm,3.7 mm, 3.8 mm, 3.9 mm, 4 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, 4.5 mm,4.6 mm, 4.7 mm, 4.8 mm, 4.9 mm, 5 mm, 5.1 mm, 5.2 mm, 5.3 mm, 5.4 mm,5.5 mm, 5.6 mm, 5.7 mm, 5.8 mm, 5.9 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm,11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 28 mm, 29 mm, 30 mm, 31mm, 32 mm, 33 mm, 34 mm, 35 mm, 36 mm, 37 mm, 38 mm, 39 mm, 40 mm, 41mm, 42 mm, 43 mm, 44 mm, 45 mm, 46 mm, 47 mm, 48 mm, 49 mm, 50 mm, 75mm, 100 mm, 150 mm, 200 mm, 250 mm, 300 mm, 350 mm, 400 mm, 450 mm, 500mm, 600 mm, 700 mm, 800 mm, 900 mm, 1000 mm, or more, or the like.

In embodiments, the length of the short axis of the device can be, forexample, 2 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm,2.8 mm, 2.9 mm, 3 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm,3.7 mm, 3.8 mm, 3.9 mm, 4 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, 4.5 mm,4.6 mm, 4.7 mm, 4.8 mm, 4.9 mm, 5 mm, 5.1 mm, 5.2 mm, 5.3 mm, 5.4 mm,5.5 mm, 5.6 mm, 5.7 mm, 5.8 mm, 5.9 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm,11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 28 mm, 29 mm, 30 mm, 31mm, 32 mm, 33 mm, 34 mm, 35 mm, 36 mm, 37 mm, 38 mm, 39 mm, 40 mm, 41mm, 42 mm, 43 mm, 44 mm, 45 mm, 46 mm, 47 mm, 48 mm, 49 mm, 50 mm, 75mm, 100 mm, or more, or the like.

Systems and devices disclosed herein can comprise an absorbent foamlayer. In embodiments the absorbent foam layer is located on theadhesive layer on the side opposite the substrate layer. In embodiments,the foam comprises water, saline, or an active agent to maintainhydration in the substrate layer.

Certain embodiments disclosed herein include a method of manufacturing aLLEC or LLEF system, the method comprising joining with a substratemultiple first reservoirs wherein selected ones of the multiple firstreservoirs include a reducing agent, and wherein first reservoirsurfaces of selected ones of the multiple first reservoirs are proximateto a first substrate surface; and joining with the substrate multiplesecond reservoirs wherein selected ones of the multiple secondreservoirs include an oxidizing agent, and wherein second reservoirsurfaces of selected ones of the multiple second reservoirs areproximate to the first substrate surface, wherein joining the multiplefirst reservoirs and joining the multiple second reservoirs comprisesjoining using tattooing. In embodiments the substrate can comprisegauzes comprising dots or electrodes.

Further embodiments can include a method of manufacturing a LLEC or LLEFsystem, the method comprising joining with a substrate multiple firstreservoirs wherein selected ones of the multiple first reservoirsinclude a reducing agent, and wherein first reservoir surfaces ofselected ones of the multiple first reservoirs are proximate to a firstsubstrate surface; and joining with the substrate multiple secondreservoirs wherein selected ones of the multiple second reservoirsinclude an oxidizing agent, and wherein second reservoir surfaces ofselected ones of the multiple second reservoirs are proximate to thefirst substrate surface, wherein joining the multiple first reservoirsand joining the multiple second reservoirs comprises: combining themultiple first reservoirs, the multiple second reservoirs, and multipleparallel insulators to produce a pattern repeat arranged in a firstdirection across a plane, the pattern repeat including a sequence of afirst one of the parallel insulators, one of the multiple firstreservoirs, a second one of the parallel insulators, and one of themultiple second reservoirs; and weaving multiple transverse insulatorsthrough the first parallel insulator, the one first reservoir, thesecond parallel insulator, and the one second reservoir in a seconddirection across the plane to produce a woven apparatus.

In embodiments “ink” or “paint” can comprise any conductive materialsuch as a solution suitable for forming an electrode on a surface, suchas a conductive metal solution. In embodiments “printing” or “painted”can comprise any method of applying a conductive material such as aconductive liquid material to a material upon which a matrix is desired,such as a fabric.

In embodiments printing devices can be used to produce LLEC or LLEFsystems disclosed herein. For example, inkjet or “3D” printers can beused to produce embodiments.

In certain embodiments the binders or inks used to produce LLEC or LLEFsystems disclosed herein can include, for example, poly cellulose inks,poly acrylic inks, poly urethane inks, silicone inks, and the like. Inembodiments the type of ink used can determine the release rate ofelectrons from the reservoirs. In embodiments various materials can beadded to the ink or binder such as, for example, conductive or resistivematerials can be added to alter the shape or strength of the electricfield. Other materials, such as silicone, can be added, for example toenhance scar reduction. Such materials can also be added to the spacesbetween reservoirs.

In embodiments, fabric embodiments disclosed herein can be woven of atleast two types of fibers; fibers comprising sections treated or coatedwith a substance capable of forming a positive electrode; and fiberscomprising sections treated or coated with a substance capable offorming a negative electrode. The fabric can further comprise fibersthat do not form an electrode. Long lengths of fibers can be woventogether to form fabrics. For example, the fibers can be woven togetherto form a regular pattern of positive and negative electrodes.

Embodiments disclosed herein include a multilayer fabric, for example alayer that can produce an LLEC/LLEF as described herein, a hydrationlayer, and a waterproof layer.

In some embodiments, a LLEC or LLEF system can be integrated into agarment or affixed to the garment. For example, the LLEC or LLEF systemcan be printed directly on a garment while being manufactured or affixedto garment after it has been manufactured. In another embodiment, a LLECor LLEF system can be removed from a garment for the ability andreplaced with a new system as needed.

Certain embodiments are designed for universal conformability with anyarea of the body, for example a flat area or a contoured area. Inembodiments the dressings are configured to conform to the area to betreated, for example by producing the dressing in particular shapesincluding “slits” or discontinuous regions. In embodiments the dressingcan be produced in a U shape wherein the “arms” of the U aresubstantially equal in length as compared to the “base” of the U. Inembodiments the dressing can be produced in a U shape wherein the “arms”of the U are substantially longer in length as compared to the “base” ofthe U. In embodiments the dressing can be produced in a U shape whereinthe “arms” of the U are substantially shorter in length as compared tothe “base” of the U. In embodiments the dressing can be produced in an Xshape wherein the “arms” of the X are substantially equal in length. Inembodiments the universal dressing can be used to treat, for example,muscles, or skin, for example to treat “road rash.”

The systems and devices can comprise corresponding or interlockingperimeter areas to assist the devices in maintaining their position onthe patient and/or their position relative to each other. In certainembodiments, the systems and devices can comprise a port or ports toprovide access to the treatment area beneath the device.

LLEC/LLEF Systems, Devices, and Methods of Use

Embodiments disclosed herein include LLEC and LLEF systems that canpromote and/or accelerate the muscle recovery process and optimizemuscle performance. For example, muscles work when calcium ions arereleased, which trigger muscle cells to contract. Proteins called actinand myosin form filaments, which form cross-bridges during contraction.The actin and myosin filaments pull past each other when a flood ofcalcium ions signals contraction, and this causes the muscle sheath tobecome shorter. This leads all the sheaths (called “sarcomeres”) toshorten, and the contraction is synchronized across the entire muscle.The contracting muscles pull on tendons, which in turn pull on the bonesto which they are attached. All muscle contractions are triggered byelectrical impulses which travel from the brain to the nerve endings incontact with the actin and myosin filaments. Embodiments disclosedherein can increase intracellular calcium levels by exposing cells tothe electric field produced by disclosed embodiments.

Further, embodiments disclosed herein can direct cell migration.

Further embodiments can increase cellular protein sulfhydryl levels andcellular glucose uptake. Increased glucose uptake can result in greatermitochondrial activity and thus increased glucose utilization.

Disclosed methods of use comprise application of a system or devicedescribed herein to a tissue, for example a joint or muscle or musclegroup. In embodiments, the application can be performed prior to,during, or after use of the muscle or muscle group to be treated. Forexample, a shoulder can be treated prior to engaging in an athleticactivity, for example pitching a baseball.

Disclosed embodiments can prevent or limit muscle injury, for example byactivating enzymes that aid in the muscle recovery process, increasingglucose uptake, driving redox signaling, increasing H₂O₂ production,increasing cellular protein sulfhydryl levels, and increasing (IGF)-1 Rphosphorylation.

Disclosed embodiments can repair muscle damage (for example such as canoccur during a workout), for example by activating enzymes that aid inthe muscle recovery process, increasing glucose uptake, driving redoxsignaling, increasing H₂O₂ production, increasing cellular proteinsulfhydryl levels, and increasing (IGF)-1 R phosphorylation.

Disclosed embodiments can improve muscle recovery, for example byactivating enzymes that aid in the muscle recovery process, increasingglucose uptake, driving redox signaling, increasing H₂O₂ production,increasing cellular protein sulfhydryl levels, and increasing (IGF)-1 Rphosphorylation.

Disclosed embodiments can improve muscle function, for example byactivating enzymes, increasing glucose uptake, driving redox signaling,increasing H₂O₂ production, increasing cellular protein sulfhydryllevels, and increasing (IGF)-1 R phosphorylation.

Disclosed embodiments can improve athletic performance, for example byactivating enzymes, increasing glucose uptake, driving redox signaling,increasing H₂O₂ production, increasing cellular protein sulfhydryllevels, and increasing (IGF)-1 R phosphorylation.

Disclosed embodiments can produce an electrical stimulus and/or canelectro-motivate, electro-conduct, electro-induct, electro-transport,and/or electrophorese one or more therapeutic materials in areas oftarget tissue (e.g., iontophoresis), and/or can cause one or morebiologic or other materials in proximity to, on or within target tissueto be rejuvenated. Further disclosure relating to materials that canproduce an electrical stimulus can be found in U.S. Pat. No. 7,662,176entitled FOOTWEAR APPARATUS AND METHODS OF MANUFACTURE AND USE issuedFeb. 16, 2010, which is incorporated herein by reference in itsentirety.

Methods disclosed herein can include applying a disclosed embodiment toan area to be treated. Embodiments can include selecting or identifyinga patient in need of treatment. In embodiments, methods disclosed hereincan include application of a device disclosed herein to an area to betreated.

In embodiments, disclosed methods include application to the treatmentarea or the device of an antibacterial. In embodiments the antibacterialcan be, for example, alcohols, aldehydes, halogen-releasing compounds,peroxides, anilides, biguanides, bisphenols, halophenols, heavy metals,phenols and cresols, quaternary ammonium compounds, and the like. Inembodiments the antibacterial agent can comprise, for example, ethanol,isopropanol, glutaraldehyde, formaldehyde, chlorine compounds, iodinecompounds, hydrogen peroxide, ozone, peracetic acid, formaldehyde,ethylene oxide, triclocarban, chlorhexidine, alexidine, polymericbiguanides, triclosan, hexachlorophene, PCMX (p-chloro-m-xylenol),silver compounds, mercury compounds, phenol, cresol, cetrimide,benzalkonium chloride, cetylpyridinium chloride, ceftolozane/tazobactam,ceftazidime/avibactam, ceftaroline/avibactam, imipenem/MK-7655,plazomicin, eravacycline, brilacidin, and the like.

In embodiments, compounds that modify resistance to commonantibacterials can be employed. For example, some resistance-modifyingagents may inhibit multidrug resistance mechanisms, such as drug effluxfrom the cell, thus increasing the susceptibility of bacteria to anantibacterial. In embodiments, these compounds can includePhe-Arg-β-naphthylamide, or β-lactamase inhibitors such as clavulanicacid and sulbactam.

In embodiments, the system can also be used for preventative treatmentof tissue injuries. Preventative treatment can include preventing thereoccurrence of previous muscle injuries. For example, a garment can beshaped to fit a patient's shoulder to prevent recurrence of a deltoidinjury.

EXAMPLES

The following non-limiting examples are provided for illustrativepurposes only in order to facilitate a more complete understanding ofrepresentative embodiments. These examples should not be construed tolimit any of the embodiments described in the present specification.

Example 1 Cell Migration Assay

The in vitro scratch assay is a well-developed method to measure cellmigration in vitro. The basic steps involve creating a “scratch” in acell monolayer, capturing images at the beginning and at regularintervals during cell migration to close the scratch, and comparing theimages to quantify the migration rate of the cells. Compared to othermethods, the in vitro scratch assay is particularly suitable for studieson the effects of cell-matrix and cell-cell interactions on cellmigration, mimic cell migration during wound healing in vivo and arecompatible with imaging of live cells during migration to monitorintracellular events if desired. In addition to monitoring migration ofhomogenous cell populations, this method has also been adopted tomeasure migration of individual cells in the leading edge of thescratch.

Human keratinocytes were plated under plated under placebo or a LLECsystem as described herein (labeled “PROCELLERA®”). Cells were alsoplated under silver-only or zinc-only dressings. After 24 hours, thescratch assay was performed. Cells plated under the PROCELLERA® devicedisplayed increased migration into the “scratched” area as compared toany of the zinc, silver, or placebo dressings. After 9 hours, the cellsplated under the PROCELLERA® device had almost “closed” the scratch.This demonstrates the importance of electrical activity to cellmigration and infiltration.

In addition to the scratch test, genetic expression was tested.Increased insulin growth factor (IGF)-1 R phosphorylation wasdemonstrated by the cells plated under the PROCELLERA® device ascompared to cells plated under insulin growth factor alone.

Integrin accumulation also affects cell migration. An increase inintegrin accumulation was achieved with the LLEC system. Integrin isnecessary for cell migration, and is found on the leading edge ofmigrating cell.

Thus, the tested LLEC system enhanced cellular migration and IGF-1R/integrin involvement. This involvement demonstrates the effect thatthe LLEC system had upon cell receptors involved with the wound healingprocess.

Example 2 Wound Care Study

The medical histories of patients who received “standard-of-care” woundtreatment (“SOC”; n=20), or treatment with a LLEC device as disclosedherein (n=18), were reviewed. The wound care device used in the presentstudy consisted of a discrete matrix of silver and zinc dots. Asustained voltage of approximately 0.8 V was generated between the dots.The electric field generated at the device surface was measured to be0.2-1.0 V, 10-50 μA.

Wounds were assessed until closed or healed. The number of days to woundclosure and the rate of wound volume reduction were compared. Patientstreated with LLEC received one application of the device each week, ormore frequently in the presence of excessive wound exudate, inconjunction with appropriate wound care management. The LLEC was keptmoist by saturating with normal saline or conductive hydrogel.Adjunctive therapies (such as negative pressure wound therapy [NPWT],etc.) were administered with SOC or with the use of LLEC unlesscontraindicated. The SOC group received the standard of care appropriateto the wound, for example antimicrobial dressings, barrier creams,alginates, silver dressings, absorptive foam dressings, hydrogel,enzymatic debridement ointment, NPWT, etc. Etiology-specific care wasadministered on a case-by-case basis. Dressings were applied at weeklyintervals or more. The SOC and LLEC groups did not differ significantlyin gender, age, wound types or the length, width, and area of theirwounds.

Wound dimensions were recorded at the beginning of the treatment, aswell as interim and final patient visits. Wound dimensions, includinglength (L), width (W) and depth (D) were measured, with depth measuredat the deepest point. Wound closure progression was also documentedthrough digital photography. Determining the area of the wound wasperformed using the length and width measurements of the wound surfacearea.

Closure was defined as 100% epithelialization with visible effacement ofthe wound. Wounds were assessed 1 week post-closure to ensure continuedprogress toward healing during its maturation and remodeling phase.

Wound types included in this study were diverse in etiology anddimensions, thus the time to heal for wounds was distributed over a widerange (9-124 days for SOC, and 3-44 days for the LLEC group).Additionally, the patients often had multiple co-morbidities, includingdiabetes, renal disease, and hypertension. The average number of days towound closure was 36.25 (SD=28.89) for the SOC group and 19.78(SD=14.45) for the LLEC group, p=0.036. On average, the wounds in theLLEC treatment group attained closure 45.43% earlier than those in theSOC group.

Based on the volume calculated, some wounds improved persistently whileothers first increased in size before improving. The SOC and the LLECgroups were compared to each other in terms of the number of instanceswhen the dimensions of the patient wounds increased (i.e., woundtreatment outcome degraded). In the SOC group, 10 wounds (50% for n=20)became larger during at least one measurement interval, whereas 3 wounds(16.7% for n=18) became larger in the LLEC group (p=0.018). Overall,wounds in both groups responded positively. Response to treatment wasobserved to be slower during the initial phase, but was observed toimprove as time progressed.

The LLEC wound treatment group demonstrated on average a 45.4% fasterclosure rate as compared to the SOC group. Wounds receiving SOC weremore likely to follow a “waxing-and-waning” progression in wound closurecompared to wounds in the LLEC treatment group.

Compared to localized SOC treatments for wounds, the LLEC (1) reduceswound closure time, (2) has a steeper wound closure trajectory, and (3)has a more robust wound healing trend with fewer incidence of increasedwound dimensions during the course of healing.

Example 3 LLEC Influence on Human Keratinocyte Migration

An LLEC-generated electrical field was mapped, leading to theobservation that LLEC generates hydrogen peroxide, known to drive redoxsignaling. LLEC-induced phosphorylation of redox-sensitive IGF-1 R wasdirectly implicated in cell migration. The LLEC also increasedkeratinocyte mitochondrial membrane potential.

The LLEC was made of polyester printed with dissimilar elemental metalsas described herein. It comprises alternating circular regions of silverand zinc dots, along with a proprietary, biocompatible binder added tolock the electrodes to the surface of a flexible substrate in a patternof discrete reservoirs. When the LLEC contacts an aqueous solution, thesilver positive electrode (cathode) is reduced while the zinc negativeelectrode (anode) is oxidized. The LLEC used herein consisted of metalsplaced in proximity of about 1 mm to each other thus forming a redoxcouple and generating an ideal potential on the order of 1 Volt. Thecalculated values of the electric field from the LLEC were consistentwith the magnitudes that are typically applied (1-10 V/cm) in classicalelectrotaxis experiments, suggesting that cell migration observed withthe bioelectric dressing is likely due to electrotaxis.

Measurement of the potential difference between adjacent zinc and silverdots when the LLEC is in contact with de-ionized water yielded a valueof about 0.2 Volts. Though the potential difference between zinc andsilver dots can be measured, non-intrusive measurement of the electricfield arising from contact between the LLEC and liquid medium wasdifficult. Keratinocyte migration was accelerated by exposure to anAg/Zn LLEC. Replacing the Ag/Zn redox couple with Ag or Zn alone did notreproduce the effect of keratinocyte acceleration.

Exposing keratinocytes to an LLEC for 24 h significantly increased greenfluorescence in the dichlorofluorescein (DCF) assay indicatinggeneration of reactive oxygen species under the effect of the LLEC. Todetermine whether H₂O₂ is generated specifically, keratinocytes werecultured with a LLEC or placebo for 24 h and then loaded with PF6-AM(Peroxyfluor-6 acetoxymethyl ester; an indicator of endogenous H₂O₂).Greater intracellular fluorescence was observed in the LLECkeratinocytes compared to the cells grown with placebo. Over-expressionof catalase (an enzyme that breaks down H₂O₂) attenuated the increasedmigration triggered by the LLEC. Treating keratinocytes with N-AcetylCysteine (which blocks oxidant-induced signaling) also failed toreproduce the increased migration observed with LLEC. Thus, H₂O₂signaling mediated the increase of keratinocyte migration under theeffect of the electrical stimulus.

External electrical stimulus can up-regulate the TCA (tricarboxylicacid) cycle. The stimulated TCA cycle is then expected to generate moreNADH and FADH₂ to enter into the electron transport chain and elevatethe mitochondrial membrane potential (Am). Fluorescent dyes JC-1 andTMRM were used to measure mitochondrial membrane potential. JC-1 is alipophilic dye which produces a red fluorescence with high Am and greenfluorescence when Am is low. TMRM produces a red fluorescenceproportional to Am. Treatment of keratinocytes with LLEC for 24 hdemonstrated significantly high red fluorescence with both JC-1 andTMRM, indicating an increase in mitochondrial membrane potential andenergized mitochondria under the effect of the LLEC. As a potentialconsequence of a stimulated TCA cycle, available pyruvate (the primarysubstrate for the TCA cycle) is depleted resulting in an enhanced rateof glycolysis. This can lead to an increase in glucose uptake in orderto push the glycolytic pathway forward. The rate of glucose uptake inHaCaT cells treated with LLEC was examined next. More than two foldenhancement of basal glucose uptake was observed after treatment withLLEC for 24 h as compared to placebo control.

Keratinocyte migration is known to involve phosphorylation of a numberof receptor tyrosine kinases (RTKs). To determine which RTKs areactivated as a result of LLEC, scratch assay was performed onkeratinocytes treated with LLEC or placebo for 24 h. Samples werecollected after 3 h and an antibody array that allows simultaneousassessment of the phosphorylation status of 42 RTKs was used to quantifyRTK phosphorylation. It was determined that LLEC significantly inducesIGF-1 R phosphorylation. Sandwich ELISA using an antibody againstphospho-IGF-1 R and total IGF-1 R verified this determination. Asobserved with the RTK array screening, potent induction inphosphorylation of IGF-1 R was observed 3 h post scratch under theinfluence of LLEC. IGF-1 R inhibitor attenuated the increasedkeratinocyte migration observed with LLEC treatment.

MBB (monobromobimane) alkylates thiol groups, displacing the bromine andadding a fluoresce nt tag (lamda emission=478 nm). MCB(monochlorobimane) reacts with only low molecular weight thiols such asglutathione. Fluorescence emission from UV laser-excited keratinocytesloaded with either MBB or MCB was determined for 30 min. Meanfluorescence collected from 10,000 cells showed a significant shift ofMBB fluorescence emission from cells. No significant change in MCBfluorescence was observed, indicating a change in total protein thiolbut not glutathione. HaCaT cells were treated with LLEC for 24 hfollowed by a scratch assay. Integrin expression was observed byimmuno-cytochemistry at different time points. Higher integrinexpression was observed 6 h post scratch at the migrating edge.

Consistent with evidence that cell migration requires H₂O₂ sensing, wedetermined that by blocking H₂O₂ signaling by decomposition of H₂O₂ bycatalase or ROS scavenger, N-acetyl cysteine, the increase inLLEC-driven cell migration is prevented. The observation that the LLECincreases H₂O₂ production is significant because in addition to cellmigration, hydrogen peroxide generated in the wound margin tissue isrequired to recruit neutrophils and other leukocytes to the wound,regulates monocyte function, and VEGF signaling pathway and tissuevascularization. Therefore, external electrical stimulation can be usedas an effective strategy to deliver low levels of hydrogen peroxide overtime to mimic the environment of the healing wound and thus should helpimprove wound outcomes. Another phenomenon observed duringre-epithelialization is increased expression of the integrin subunitalpha-v. There is evidence that integrin, a major extracellular matrixreceptor, polarizes in response to applied ES and thus controlsdirectional cell migration. It may be noted that there are a number ofintegrin subunits, however we chose integrin aV because of evidence ofassociation of alpha-v integrin with IGF-1 R, modulation of IGF-1receptor signaling, and of driving keratinocyte locomotion.Additionally, integrin alpha v has been reported to contain vicinalthiols that provide site for redox activation of function of theseintegrins and therefore the increase in protein thiols that we observeunder the effect of ES may be the driving force behind increasedintegrin mediated cell migration. Other possible integrins which may beplaying a role in LLEC-induced IGF-1 R mediated keratinocyte migrationare a5 integrin and a6 integrin.

Materials and Methods

Cell culture—Immortalized HaCaT human keratinocytes were grown inDulbecco's low-glucose modified Eagle's medium (Life Technologies,Gaithersburg, Md., U.S.A.) supplemented with 10% fetal bovine serum, 100U/ml penicillin, and 100 μg/ml streptomycin. The cells were maintainedin a standard culture incubator with humidified air containing 5% C02 at37° C.

Scratch assay—A cell migration assay was performed using culture inserts(IBIDI®, Verona, Wis.) according to the manufacturers instructions. Cellmigration was measured using time-lapse phase-contrast microscopyfollowing withdrawal of the insert. Images were analyzed using theAxioVision Rel 4.8 software.

N-Acetyl Cysteine Treatment—Cells were pretreated with 5 mM of the thiolantioxidant N-acetylcysteine (Sigma) for 1 h before start of the scratchassay.

IGF-1 R inhibition—When applicable, cells were preincubated with 50 nMIGF-1 R inhibitor, picropodophyllin (Calbiochem, Mass.) just prior tothe Scratch Assay.

Cellular H₂O₂ Analysis—To determine intracellular H₂O₂ levels, HaCaTcells were incubated with 5 pM PF6-AM in PBS for 20 min at roomtemperature. After loading, cells were washed twice to remove excess dyeand visualized using a Zeiss Axiovert 200M microscope.

Catalase gene delivery—HaCaT cells were transfected with 2.3×107 pfuAdCatalase or with the empty vector as control in 750 μl of media.Subsequently, 750 μl of additional media was added 4 h later and thecells were incubated for 72 h.

RTK Phosphorylation Assay—Human Phospho-Receptor Tyrosine Kinasephosphorylation was measured using Phospho-RTK Array kit (R & DSystems).

ELISA—Phosphorylated and total IGF-1 R were measured using a DuoSet ICELISA kit from R&D Systems.

Determination of Mitochondrial Membrane Potential—Mitochondrial membranepotential was measured in HaCaT cells exposed to the LLEC or placebousing TMRM or JC-1 (MitoProbe JC-1 Assay Kit for Flow Cytometry, LifeTechnologies), per manufacturers instructions for flow cytometry.

Integrin alpha V Expression—Human HaCaT cells were grown under the MCDor placebo and harvested 6 h after removing the IBIDI® insert. Stainingwas done using antibody against integrin aV (Abeam, Cambridge, Mass.).

Example 4 Generation of Superoxide

A LLEC system was tested to determine the effects on superoxide levelswhich can activate signal pathways. PROCELLERA® LLEC system increasedcellular protein sulfhydryl levels. Further, the PROCELLERA® systemincreased cellular glucose uptake in human keratinocytes. Increasedglucose uptake can result in greater mitochondrial activity and thusincreased glucose utilization, providing more energy for cellularmigration and proliferation. This can “prime” the wound healing processbefore a surgical incision is made and thus speed incision healing.

Example 5 Effect on Propionibacterium acnes

Bacterial Strains and Culture

The main bacterial strain used in this study is Propionibacterium acnesand multiple antibiotics-resistant P. acnes isolates are to beevaluated.

ATCC medium (7 Actinomyces broth) (BD) and/or ATCC medium (593 choppedmeat medium) is used for culturing P. acnes under an anaerobic conditionat 37° C. All experiments are performed under anaerobic conditions.

Culture

LNA (Leeming-Notman agar) medium is prepared and cultured at 34° C. for14 days.

Planktonic Cells

P. acnes is a relatively slow-growing, typically aero-tolerantanaerobic, Gram-positive bacterium (rod). P. acnes is cultured underanaerobic condition to determine for efficacy of an embodiment disclosedherein (PROCELLERA®). Overnight bacterial cultures are diluted withfresh culture medium supplemented with 0.1% sodium thioglycolate in PBSto 10⁵ colony forming units (CFUs). Next, the bacterial suspensions (0.5mL of about 105) are applied directly on PROCELLERA® (2″×2″) and controlfabrics in Petri-dishes under anaerobic conditions. After 0 h and 24 hpost treatments at 37° C., portions of the sample fabrics are placedinto anaerobic diluents and vigorously shaken by vortexing for 2 min.The suspensions are diluted serially and plated onto anaerobic platesunder an anaerobic condition. After 24 h incubation, the survivingcolonies are counted. The LLEC limits bacterial proliferation.

Example 6 Pre-Treatment and Post-Treatment of Surgical Procedures

Prior to surgery the patient wears a LLEC compression garment over thesurgical site, such as the upper arm or bicep area. Surgical procedurescan include procedures used to treat tenotomy, biceps tendonitis, orrotator cuff injury. The compression garment consists of an integratedlayer of standard PROCELLERA®. Prior to applying the compression garmentan activating agent can be applied. A compression sleeve or shirtprovides an intimate contact between the electrodes and the skin withminimal movement.

The LLEC compression garment with integrated PROCELLERA® can be worn for24 hours prior to surgery to initiate incision-healing process by; 1)reducing or eliminating microorganism presence around the incision site;2) increasing integrin accumulation; 3) increasing cellular proteinsulfhydryl levels; 4) increasing H₂O₂ production; and 5) up-regulatingthe TCA (tricarboxylic acid) cycle.

The same LLEC compression garment and method can also be applied to apatient's surgical site post-surgery for accelerated healing ortreatment.

Example 7 Availability of Cellular Energy and Lactate Threshold

The lactate threshold, also known as lactate inflection point oranaerobic threshold, is the exercise intensity at which lactate (morespecifically, lactic acid) starts to accumulate in the blood stream. Thereason for the acidification of the blood at high exercise intensitiesis two-fold: the high rates of ATP hydrolysis in the muscle releasehydrogen ions, as they are co-transported out of the muscle into theblood via the monocarboxylate transporter, and also bicarbonate storesin the blood begin to be used up. This happens when lactate is producedfaster than it can be removed (metabolized) in the muscle. Whenexercising at or below the lactate threshold, lactate produced by themuscles is removed by the body without it building up (e.g., aerobicrespiration). When exercising at or above the lactate threshold (e.g.anaerobic respiration), excess lactate can build up in tissue causing alower pH and soreness, called acidosis. This excess lactate build-updecreases athletic ability during exercise as well tissue recovery afterexercise and can be a primary source of post-exercise musclestiffness/pain.

Prior to exercise or activity the patient wears a LLEC compressiongarment over his body, such as the upper body using a shirt, the lowerbody using pants, or a combination of both. The compression garmentconsists of an integrated layer of standard PROCELLERA® The PROCELLERA®can be configured to penetrate into superficial muscle tissue under thecompression garment. The PROCELLERA® system increased cellular glucoseuptake. Increased glucose uptake can result in greater mitochondrialactivity and thus increased glucose utilization, providing more energyfor cellular activity to remove lactic acid from muscle tissue. It hasbeen shown that increased cellular glucose utilization can also sustainanaerobic respiration for a longer period of time during exercise, thusincreasing a person's lactate threshold. An increased lactate thresholdprevents lactate from building-up in muscle tissue, thus reducing orpreventing muscle damage and/or pain.

Example 8 Use in Muscle Damage Prevention

During exercise or activity the patient wears a LLEC compression garmentover his body, such as the upper body using a shirt, the lower bodyusing shorts, or a combination of both. The compression garment consistsof an integrated layer of standard PROCELLERA® as disclosed herein. ThePROCELLERA® can be configured to penetrate into muscle tissue under thecompression garment. The PROCELLERA® system increases cellular glucoseuptake. Increased glucose uptake can result in greater mitochondrialactivity and thus increased glucose utilization, aiding in muscle damageprevention.

Example 9 Use in Muscle Recovery

After exercise or activity the patient wears a LLEC compression garmentover his body, such as the upper body using a shirt, the lower bodyusing shorts, or a combination of both. The compression garment consistsof an integrated layer of standard PROCELLERA® as disclosed herein. ThePROCELLERA® can be configured to penetrate into muscle tissue under thecompression garment. The PROCELLERA® system increases cellular glucoseuptake. Increased glucose uptake can result in greater mitochondrialactivity and thus increased glucose utilization, aiding in musclerecovery.

Example 10 Availability of Cellular Energy and Lactate Threshold

During exercise or activity the patient wears a LLEC compression garmentover his body, such as the upper body using a shirt, the lower bodyusing pants, or a combination of both. The compression garment consistsof an integrated layer of standard PROCELLERA® The PROCELLERA® can beconfigured to penetrate into superficial muscle tissue under thecompression garment. The PROCELLERA® system increased cellular glucoseuptake. Increased glucose uptake can result in greater mitochondrialactivity and thus increased glucose utilization, providing more energyfor cellular activity to remove lactic acid from muscle tissue. It hasbeen shown that an increased cellular glucose utilization can alsosustain anaerobic respiration for a longer period of time duringexercise, thus increasing a person's lactate threshold. An increasedlactate threshold prevents lactate from building-up in muscle tissue,thus reducing or preventing muscle damage and/or pain.

In closing, it is to be understood that although aspects of the presentspecification are highlighted by referring to specific embodiments, oneskilled in the art will readily appreciate that these disclosedembodiments are only illustrative of the principles of the subjectmatter disclosed herein. Therefore, it should be understood that thedisclosed subject matter is in no way limited to a particularmethodology, protocol, and/or reagent, etc., described herein. As such,various modifications or changes to or alternative configurations of thedisclosed subject matter can be made in accordance with the teachingsherein without departing from the spirit of the present specification.Lastly, the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to limit the scope ofthe present disclosure, which is defined solely by the claims.Accordingly, embodiments of the present disclosure are not limited tothose precisely as shown and described.

Certain embodiments are described herein, including the best mode knownto the inventor for carrying out the methods and devices describedherein. Of course, variations on these described embodiments will becomeapparent to those of ordinary skill in the art upon reading theforegoing description. Accordingly, this disclosure includes allmodifications and equivalents of the subject matter recited in theclaims appended hereto as permitted by applicable law. Moreover, anycombination of the above-described embodiments in all possiblevariations thereof is encompassed by the disclosure unless otherwiseindicated herein or otherwise clearly contradicted by context.

Groupings of alternative embodiments, elements, or steps of the presentdisclosure are not to be construed as limitations. Each group member maybe referred to and claimed individually or in any combination with othergroup members disclosed herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Unless otherwise indicated, all numbers expressing a characteristic,item, quantity, parameter, property, term, and so forth used in thepresent specification and claims are to be understood as being modifiedin all instances by the term “about.” As used herein, the term “about”means that the characteristic, item, quantity, parameter, property, orterm so qualified encompasses a range of plus or minus ten percent aboveand below the value of the stated characteristic, item, quantity,parameter, property, or term. Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical indication shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques. Notwithstandingthat the numerical ranges and values setting forth the broad scope ofthe disclosure are approximations, the numerical ranges and values setforth in the specific examples are reported as precisely as possible.Any numerical range or value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Recitation of numerical ranges ofvalues herein is merely intended to serve as a shorthand method ofreferring individually to each separate numerical value falling withinthe range. Unless otherwise indicated herein, each individual value of anumerical range is incorporated into the present specification as if itwere individually recited herein.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the disclosure (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate thedisclosure and does not pose a limitation on the scope otherwiseclaimed. No language in the present specification should be construed asindicating any non-claimed element essential to the practice ofembodiments disclosed herein.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or consisting essentially of language. Whenused in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the present disclosure so claimed areinherently or expressly described and enabled herein.

The invention claimed is:
 1. A stretchable quadriceps injury treatmentdevice, comprising: a garment adapted to fit a leg of a subject, saidgarment comprising a substrate wherein the garment substrate comprises acompression fabric, wherein said compression fabric exerts a pressure ofbetween 40 mmHg and 50 mmHg on the quadriceps and a lesser pressure onthe subject's lower leg; and a plurality of biocompatible electrodesconfigured to generate at least one of a low level electric field (LLEF)or low level electric current (LLEC), wherein the biocompatibleelectrodes comprise a first array comprising a first pattern ofmicrocells formed from a first conductive material, and a second arraycomprising a second pattern of microcells formed from a secondconductive material, wherein the diameter of each microcell in the firstarray is 1.5 mm+/−1 mm and the diameter of each microcell in the secondarray is 2.5 mm+/−2 mm, and the first and second conductive materialscomprise different materials.
 2. The device of claim 1 wherein the firstarray and the second array spontaneously generate the LLEF.
 3. Thedevice of claim 2 wherein the first array and the second arrayspontaneously generate the LLEC when contacted with an electrolyticsolution.
 4. A method for treating a quadricep injury, comprising:Applying to the quadriceps a stretchable garment adapted to fit a leg ofa subject, said garment comprising a substrate comprising a compressionfabric comprising a plurality of biocompatible electrodes, wherein saidcompression fabric exerts a pressure of between 40 mmHg and 50 mmHg onthe quadriceps and a lesser pressure on the subject's lower leg, whereinsaid plurality of biocompatible electrodes comprises: a first arraycomprising a pattern of microcells comprising a first conductivematerial; and a second array comprising a pattern of microcellscomprising a second conductive material, such arrays capable of definingat least one voltaic cell for spontaneously generating at least oneelectrical current with the conductive material of the first array whensaid first and second arrays are introduced to an electrolytic solution,wherein the diameter of each microcell is in the first array is 1.5mm+/−1 mm and the diameter of each microcell in the second array is 2.5mm+/−2 mm and the first and second conductive materials comprisedifferent materials; wherein the garment substrate provides a low levelelectric current (LLEC) of between 1 and 200 micro-amperes to thequadriceps for muscle recovery.
 5. The method of claim 4, wherein saidtreating muscle comprises increasing cellular protein sulfhydryl levels.6. The method of claim 4, wherein said treating muscle comprisesincreasing cellular glucose uptake to provide an increased availabilityof cellular energy.
 7. A method for preventing quadriceps injury,comprising: Applying to the quadriceps a stretchable garment adapted tofit a leg of a subject, said garment comprising a substrate comprising acompression fabric comprising a plurality of biocompatible electrodes,wherein said compression fabric exerts a pressure of between 40 mmHg and50 mmHg on the quadriceps and a lesser pressure on the subject's lowerleg; wherein said plurality of biocompatible electrodes comprises: afirst array comprising a pattern of microcells comprising a firstconductive material; and a second array comprising a pattern ofmicrocells comprising a second conductive material, such arrays capableof defining at least one voltaic cell for spontaneously generating atleast one electrical current with the conductive material of the firstarray when said first and second arrays are introduced to anelectrolytic solution, wherein the diameter of each microcell is in thefirst array is 1.5 mm+/−1 mm and the diameter of each microcell in thesecond array is 2.5 mm+/−2 mm and the first and second conductivematerials comprise different materials; wherein the garment substrateprovides a low level micro-current (LLEC) of between 1 and 200micro-amperes to the quadriceps.